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Record Information
Version2.0
Creation Date2009-07-30 17:59:09 UTC
Update Date2014-12-24 20:26:08 UTC
Accession NumberT3D3533
Identification
Common NameSorafenib
ClassSmall Molecule
DescriptionSorafenib (rINN), marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received 'Fast Track' designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer), and has since performed well in Phase III trials. Sorafenib is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor. A growing number of drugs target most of these pathways. The originality of Sorafenib lays in its simultaneous targeting of the Raf/Mek/Erk pathway.
Compound Type
  • Amide
  • Amine
  • Anticancer Agent
  • Antineoplastic Agent
  • Drug
  • Ester
  • Ether
  • Metabolite
  • Organic Compound
  • Organochloride
  • Organofluoride
  • Protein Kinase Inhibitor
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
4-(4-((((4-Chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-2-pyridinecarboxamide
N-(4-Chloro-3-(trifluoromethyl)phenyl)-n'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea
Nexavar
Sorafenib tosylate
Sorafenibum
Chemical FormulaC21H16ClF3N4O3
Average Molecular Mass464.825 g/mol
Monoisotopic Mass464.086 g/mol
CAS Registry Number284461-73-0
IUPAC Name4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide
Traditional Namesorafenib
SMILESCNC(=O)C1=NC=CC(OC2=CC=C(NC(O)=NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1
InChI IdentifierInChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)
InChI KeyInChIKey=MLDQJTXFUGDVEO-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
KingdomOrganic compounds
Super ClassOrganic oxygen compounds
ClassOrganooxygen compounds
Sub ClassEthers
Direct ParentDiarylethers
Alternative Parents
Substituents
  • Diaryl ether
  • Trifluoromethylbenzene
  • N-phenylurea
  • Pyridine carboxylic acid or derivatives
  • Pyridinecarboxamide
  • 2-heteroaryl carboxamide
  • Phenoxy compound
  • Phenol ether
  • Halobenzene
  • Chlorobenzene
  • Benzenoid
  • Pyridine
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • Urea
  • Secondary carboxylic acid amide
  • Carbonic acid derivative
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Carboxylic acid derivative
  • Organic nitrogen compound
  • Organopnictogen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Organofluoride
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Alkyl halide
  • Alkyl fluoride
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilityInsoluble
LogP3.8
Predicted Properties
PropertyValueSource
Water Solubility0.0017 g/LALOGPS
logP4.12ALOGPS
logP4.34ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)11.55ChemAxon
pKa (Strongest Basic)2.03ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area92.35 ŲChemAxon
Rotatable Bond Count6ChemAxon
Refractivity114.52 m³·mol⁻¹ChemAxon
Polarizability41.11 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-022j-2972400000-d028d5e696594206a526JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-014i-0130900000-b23ba9e8bd12e0916813JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00rg-0490300000-db91bca5efaa6389647bJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4r-3950000000-ae1180c0143c97f5e1f8JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-01ox-0550900000-6151f8a0f4158ca5b6afJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0006-0890300000-869fd311854027fc3daeJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-3910000000-ad78334ecc783ea7c79aJSpectraViewer
Toxicity Profile
Route of ExposureThe mean relative bioavailability is 38-49% for the tablet form, when compared to an oral solution. Sorafenib reached peak plasma levels in 3 hours following oral administration. With a high-fat meal, bioavailability is reduced by 29% compared to administration in the fasted state.
Mechanism of ToxicitySorafenib interacts with multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß). Several of these kinases are thought to be involved in angiogenesis, thus sorafenib reduces blood flow to the tumor. Sorafenib is unique in targeting the Raf/Mek/Erk pathway. By inhibiting these kinases, genetic transcription involving cell proliferation and angiogenesis is inhibited.
MetabolismSorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady- state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state. Route of Elimination: Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites. Half Life: 25-48 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesSorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.
Minimum Risk LevelNot Available
Health EffectsHand-foot skin reaction and rash represent the most common adverse reactions; may increase the risk of bleeding (2)
SymptomsThe highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic events. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals.
TreatmentThere is no specific treatment for NEXAVAR (Sorafenib ) overdose. (2)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00398
HMDB IDHMDB14542
PubChem Compound ID216239
ChEMBL IDCHEMBL1336
ChemSpider ID187440
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID50924
BioCyc IDNot Available
CTD IDNot Available
Stitch IDSorafenib
PDB IDBAX
ACToR IDNot Available
Wikipedia LinkSorafenib
References
Synthesis Reference

Ales Gavenda, Alexandr Jegorov, Pierluigi Rossetto, Peter Lindsay MacDonald, Augusto Canavesi, “POLYMORPHS OF SORAFENIB TOSYLATE AND SORAFENIB HEMI-TOSYLATE, AND PROCESSES FOR PREPARATION THEREOF.” U.S. Patent US20090192200, issued July 30, 2009.

MSDST3D3533.pdf
General References
  1. FDA label
  2. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Protein tyrosine kinase activity
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.
Gene Name:
FGFR1
Uniprot ID:
P11362
Molecular Weight:
91866.935 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation2.5 uMNot AvailableBindingDB 16673
Dissociation2.8 uMNot AvailableBindingDB 16673
References
  1. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109. [15466206 ]
  2. Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M: BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006 Mar 1;98(5):326-34. [16507829 ]
  3. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006 Oct;5(10):835-44. [17016424 ]
  4. Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ: A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005 Mar;23(3):329-36. Epub 2005 Feb 13. [15711537 ]
  5. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP: A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358. [18183025 ]
  6. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4. [19654408 ]
  7. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP: Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990. [22037378 ]
General Function:
Transmembrane receptor protein tyrosine kinase activity
Specific Function:
Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration.
Gene Name:
RET
Uniprot ID:
P07949
Molecular Weight:
124317.465 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation0.0074 uMNot AvailableBindingDB 16673
Dissociation0.013 uMNot AvailableBindingDB 16673
Dissociation0.022 uMNot AvailableBindingDB 16673
Dissociation0.039 uMNot AvailableBindingDB 16673
Dissociation7.4 uMNot AvailableBindingDB 16673
Dissociation13 uMNot AvailableBindingDB 16673
References
  1. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109. [15466206 ]
  2. Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M: BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006 Mar 1;98(5):326-34. [16507829 ]
  3. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006 Oct;5(10):835-44. [17016424 ]
  4. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP: A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358. [18183025 ]
  5. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP: Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990. [22037378 ]
  6. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4. [19654408 ]
  7. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
General Function:
Vegf-b-activated receptor activity
Specific Function:
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Likewise, isoforms lacking a transmembrane domain, such as isoform 2, isoform 3 and isoform 4, may function as decoy receptors for VEGFA. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Isoform 1 phosphorylates PLCG. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1. Isoform 7 has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion.
Gene Name:
FLT1
Uniprot ID:
P17948
Molecular Weight:
150767.185 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation0.031 uMNot AvailableBindingDB 16673
Dissociation31 uMNot AvailableBindingDB 16673
References
  1. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109. [15466206 ]
  2. Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M: BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006 Mar 1;98(5):326-34. [16507829 ]
  3. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006 Oct;5(10):835-44. [17016424 ]
  4. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP: A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358. [18183025 ]
  5. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4. [19654408 ]
  6. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP: Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990. [22037378 ]
  7. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
General Function:
Vascular endothelial growth factor-activated receptor activity
Specific Function:
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.
Gene Name:
KDR
Uniprot ID:
P35968
Molecular Weight:
151525.555 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.000021 uMNot AvailableBindingDB 16673
Inhibitory0.00012 uMNot AvailableBindingDB 16673
Inhibitory0.022 uMNot AvailableBindingDB 16673
Dissociation0.059 uMNot AvailableBindingDB 16673
Dissociation0.093 uMNot AvailableBindingDB 16673
Dissociation59 uMNot AvailableBindingDB 16673
References
  1. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP: A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358. [18183025 ]
  2. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4. [19654408 ]
  3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP: Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990. [22037378 ]
  4. Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ: A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005 Mar;23(3):329-36. Epub 2005 Feb 13. [15711537 ]
  5. McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C, Lamb J, Archibald H, Raudales R, Tam A, Lee D, Rothenberg SM, Supko JG, Sordella R, Ulkus LE, Iafrate AJ, Maheswaran S, Njauw CN, Tsao H, Drew L, Hanke JH, Ma XJ, Erlander MG, Gray NS, Haber DA, Settleman J: Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41. Epub 2007 Dec 6. [18077425 ]
  6. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
  7. Iwata H, Imamura S, Hori A, Hixon MS, Kimura H, Miki H: Biochemical characterization of a novel type-II VEGFR2 kinase inhibitor: comparison of binding to non-phosphorylated and phosphorylated VEGFR2. Bioorg Med Chem. 2011 Sep 15;19(18):5342-51. doi: 10.1016/j.bmc.2011.08.002. Epub 2011 Aug 6. [21885287 ]
General Function:
Vascular endothelial growth factor binding
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor.
Gene Name:
PDGFRB
Uniprot ID:
P09619
Molecular Weight:
123966.895 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation0.037 uMNot AvailableBindingDB 16673
Dissociation0.041 uMNot AvailableBindingDB 16673
Dissociation37 uMNot AvailableBindingDB 16673
References
  1. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP: A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358. [18183025 ]
  2. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4. [19654408 ]
  3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP: Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990. [22037378 ]
  4. Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ: A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005 Mar;23(3):329-36. Epub 2005 Feb 13. [15711537 ]
  5. McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C, Lamb J, Archibald H, Raudales R, Tam A, Lee D, Rothenberg SM, Supko JG, Sordella R, Ulkus LE, Iafrate AJ, Maheswaran S, Njauw CN, Tsao H, Drew L, Hanke JH, Ma XJ, Erlander MG, Gray NS, Haber DA, Settleman J: Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41. Epub 2007 Dec 6. [18077425 ]
  6. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
General Function:
Vascular endothelial growth factor-activated receptor activity
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.
Gene Name:
FLT3
Uniprot ID:
P36888
Molecular Weight:
112902.51 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation0.0045 uMNot AvailableBindingDB 16673
Dissociation0.011 uMNot AvailableBindingDB 16673
Dissociation0.013 uMNot AvailableBindingDB 16673
Dissociation0.017 uMNot AvailableBindingDB 16673
Dissociation0.02 uMNot AvailableBindingDB 16673
Dissociation0.03 uMNot AvailableBindingDB 16673
Dissociation0.079 uMNot AvailableBindingDB 16673
Dissociation0.082 uMNot AvailableBindingDB 16673
References
  1. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP: Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990. [22037378 ]
  2. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP: A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358. [18183025 ]
  3. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4. [19654408 ]
  4. Chao Q, Sprankle KG, Grotzfeld RM, Lai AG, Carter TA, Velasco AM, Gunawardane RN, Cramer MD, Gardner MF, James J, Zarrinkar PP, Patel HK, Bhagwat SS: Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1 ,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor. J Med Chem. 2009 Dec 10;52(23):7808-16. doi: 10.1021/jm9007533. [19754199 ]
  5. Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ: A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005 Mar;23(3):329-36. Epub 2005 Feb 13. [15711537 ]
  6. McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C, Lamb J, Archibald H, Raudales R, Tam A, Lee D, Rothenberg SM, Supko JG, Sordella R, Ulkus LE, Iafrate AJ, Maheswaran S, Njauw CN, Tsao H, Drew L, Hanke JH, Ma XJ, Erlander MG, Gray NS, Haber DA, Settleman J: Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41. Epub 2007 Dec 6. [18077425 ]
General Function:
Protein serine/threonine kinase activity
Specific Function:
Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, and thereby contributes to the MAP kinase signal transduction pathway.
Gene Name:
BRAF
Uniprot ID:
P15056
Molecular Weight:
84436.135 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.022 uMNot AvailableBindingDB 16673
Dissociation0.26 uMNot AvailableBindingDB 16673
Dissociation0.54 uMNot AvailableBindingDB 16673
Dissociation260 uMNot AvailableBindingDB 16673
Dissociation540 uMNot AvailableBindingDB 16673
References
  1. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP: A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358. [18183025 ]
  2. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP: Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990. [22037378 ]
  3. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4. [19654408 ]
  4. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
  5. Knight ZA, Shokat KM: Features of selective kinase inhibitors. Chem Biol. 2005 Jun;12(6):621-37. [15975507 ]
General Function:
Vascular endothelial growth factor-activated receptor activity
Specific Function:
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.
Gene Name:
FLT4
Uniprot ID:
P35916
Molecular Weight:
152755.94 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation0.016 uMNot AvailableBindingDB 16673
Dissociation0.095 uMNot AvailableBindingDB 16673
References
  1. Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ: A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005 Mar;23(3):329-36. Epub 2005 Feb 13. [15711537 ]
  2. McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C, Lamb J, Archibald H, Raudales R, Tam A, Lee D, Rothenberg SM, Supko JG, Sordella R, Ulkus LE, Iafrate AJ, Maheswaran S, Njauw CN, Tsao H, Drew L, Hanke JH, Ma XJ, Erlander MG, Gray NS, Haber DA, Settleman J: Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41. Epub 2007 Dec 6. [18077425 ]
  3. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP: A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358. [18183025 ]
  4. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4. [19654408 ]
  5. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP: Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990. [22037378 ]
General Function:
Protein serine/threonine kinase activity
Specific Function:
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation.
Gene Name:
RAF1
Uniprot ID:
P04049
Molecular Weight:
73051.025 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation0.23 uMNot AvailableBindingDB 16673
Dissociation230 uMNot AvailableBindingDB 16673
References
  1. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP: A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358. [18183025 ]
  2. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4. [19654408 ]
  3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP: Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990. [22037378 ]
  4. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
General Function:
Serotonin receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of 5-hydroxytryptamine release and in the regulation of dopamine and 5-hydroxytryptamine metabolism. Plays a role in the regulation of dopamine and 5-hydroxytryptamine levels in the brain, and thereby affects neural activity, mood and behavior. Plays a role in the response to anxiogenic stimuli.
Gene Name:
HTR1A
Uniprot ID:
P08908
Molecular Weight:
46106.335 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory1.181 uMNot AvailableBindingDB 16673
References
  1. Lin X, Huang XP, Chen G, Whaley R, Peng S, Wang Y, Zhang G, Wang SX, Wang S, Roth BL, Huang N: Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors. J Med Chem. 2012 Jun 28;55(12):5749-59. doi: 10.1021/jm300338m. Epub 2012 Jun 19. [22694093 ]
General Function:
Virus receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores. Affects neural activity, perception, cognition and mood. Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction.(Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV.
Gene Name:
HTR2A
Uniprot ID:
P28223
Molecular Weight:
52602.58 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory1.959 uMNot AvailableBindingDB 16673
References
  1. Lin X, Huang XP, Chen G, Whaley R, Peng S, Wang Y, Zhang G, Wang SX, Wang S, Roth BL, Huang N: Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors. J Med Chem. 2012 Jun 28;55(12):5749-59. doi: 10.1021/jm300338m. Epub 2012 Jun 19. [22694093 ]
General Function:
Serotonin receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various ergot alkaloid derivatives and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of dopamine and 5-hydroxytryptamine release, 5-hydroxytryptamine uptake and in the regulation of extracellular dopamine and 5-hydroxytryptamine levels, and thereby affects neural activity. May play a role in the perception of pain. Plays a role in the regulation of behavior, including impulsive behavior. Required for normal proliferation of embryonic cardiac myocytes and normal heart development. Protects cardiomyocytes against apoptosis. Plays a role in the adaptation of pulmonary arteries to chronic hypoxia. Plays a role in vasoconstriction. Required for normal osteoblast function and proliferation, and for maintaining normal bone density. Required for normal proliferation of the interstitial cells of Cajal in the intestine.
Gene Name:
HTR2B
Uniprot ID:
P41595
Molecular Weight:
54297.41 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.056 uMNot AvailableBindingDB 16673
References
  1. Lin X, Huang XP, Chen G, Whaley R, Peng S, Wang Y, Zhang G, Wang SX, Wang S, Roth BL, Huang N: Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors. J Med Chem. 2012 Jun 28;55(12):5749-59. doi: 10.1021/jm300338m. Epub 2012 Jun 19. [22694093 ]
General Function:
Serotonin receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. Plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress. Plays a role in insulin sensitivity and glucose homeostasis.
Gene Name:
HTR2C
Uniprot ID:
P28335
Molecular Weight:
51820.705 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.417 uMNot AvailableBindingDB 16673
References
  1. Lin X, Huang XP, Chen G, Whaley R, Peng S, Wang Y, Zhang G, Wang SX, Wang S, Roth BL, Huang N: Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors. J Med Chem. 2012 Jun 28;55(12):5749-59. doi: 10.1021/jm300338m. Epub 2012 Jun 19. [22694093 ]
General Function:
Serotonin receptor activity
Specific Function:
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins.
Gene Name:
HTR5A
Uniprot ID:
P47898
Molecular Weight:
40254.69 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory3.296 uMNot AvailableBindingDB 16673
References
  1. Lin X, Huang XP, Chen G, Whaley R, Peng S, Wang Y, Zhang G, Wang SX, Wang S, Roth BL, Huang N: Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors. J Med Chem. 2012 Jun 28;55(12):5749-59. doi: 10.1021/jm300338m. Epub 2012 Jun 19. [22694093 ]
General Function:
Serotonin receptor activity
Specific Function:
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. It has a high affinity for tricyclic psychotropic drugs (By similarity). Controls pyramidal neurons migration during corticogenesis, through the regulation of CDK5 activity (By similarity). Is an activator of TOR signaling (PubMed:23027611).
Gene Name:
HTR6
Uniprot ID:
P50406
Molecular Weight:
46953.625 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory6.213 uMNot AvailableBindingDB 16673
References
  1. Lin X, Huang XP, Chen G, Whaley R, Peng S, Wang Y, Zhang G, Wang SX, Wang S, Roth BL, Huang N: Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors. J Med Chem. 2012 Jun 28;55(12):5749-59. doi: 10.1021/jm300338m. Epub 2012 Jun 19. [22694093 ]
General Function:
Serotonin receptor activity
Specific Function:
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase.
Gene Name:
HTR7
Uniprot ID:
P34969
Molecular Weight:
53554.43 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory7.071 uMNot AvailableBindingDB 16673
References
  1. Lin X, Huang XP, Chen G, Whaley R, Peng S, Wang Y, Zhang G, Wang SX, Wang S, Roth BL, Huang N: Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors. J Med Chem. 2012 Jun 28;55(12):5749-59. doi: 10.1021/jm300338m. Epub 2012 Jun 19. [22694093 ]
General Function:
Signal transducer activity
Specific Function:
Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress.
Gene Name:
PLK2
Uniprot ID:
Q9NYY3
Molecular Weight:
78235.87 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory30 uMNot AvailableBindingDB 16673
References
  1. Johnson EF, Stewart KD, Woods KW, Giranda VL, Luo Y: Pharmacological and functional comparison of the polo-like kinase family: insight into inhibitor and substrate specificity. Biochemistry. 2007 Aug 21;46(33):9551-63. Epub 2007 Jul 27. [17655330 ]
General Function:
Transmembrane receptor protein tyrosine kinase activity
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.
Gene Name:
KIT
Uniprot ID:
P10721
Molecular Weight:
109863.655 Da