This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Name
AMG-510
Accession Number
DB15569
Description

AMG-510 is an acrylamide derived KRAS inhibitor developed by Amgen and is currently undergoing clinical trials for solid tumors with KRAS G12C mutations.1,3 This mutation makes up >50% of all KRAS mutations.2 It is the first experimental KRAS inhibitor.1

The drug MRTX849 is also currently being developed and has the same target.1

Type
Small Molecule
Groups
Investigational
Structure
Thumb
Weight
Average: 560.606
Monoisotopic: 560.234745176
Chemical Formula
C30H30F2N6O3
Synonyms
  • Kras G12C inhibitor 9
External IDs
  • AMG 510
  • AMG-510
  • AMG510

Pharmacology

Pharmacology
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Indication

AMG-510 is being investigated for the treatment of KRAS G12C mutant non small cell lung cancer, colorectal cancer, and appendix cancer.1

Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics
Not Available
Mechanism of action

Normally GTP binds to KRAS, activating the protein and promoting effectors to the MAP kinase pathway.3 GTP is hydrolyzed to GDP, and KRAS is inactivated.4 KRAS G12C mutations impair hydrolysis of GTP, leaving it in the active form.4

AMG-510 binds to the cysteine residue in KRAS G12C mutations, holding the protein in its inactive form.1 This mutation is present in 13% of non small cell lung cancer, 3% of colorectal and appendix cancer, and 1-3% of solid tumors.1

TargetActionsOrganism
AGTPase KRas
inhibitor
Humans
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half-life
Not Available
Clearance
Not Available
Adverse Effects
Medicalerrors
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Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Not Available
Classification
Not classified

Chemical Identifiers

UNII
2B2VM6UC8G
CAS number
2252403-56-6
InChI Key
NXQKSXLFSAEQCZ-SFHVURJKSA-N
InChI
InChI=1S/C30H30F2N6O3/c1-6-23(40)36-12-13-37(18(5)15-36)28-19-14-21(32)26(24-20(31)8-7-9-22(24)39)34-29(19)38(30(41)35-28)27-17(4)10-11-33-25(27)16(2)3/h6-11,14,16,18,39H,1,12-13,15H2,2-5H3/t18-/m0/s1
IUPAC Name
6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-1H,2H-pyrido[2,3-d]pyrimidin-2-one
SMILES
CC(C)C1=NC=CC(C)=C1N1C(=O)N=C(N2CCN(C[C@@H]2C)C(=O)C=C)C2=CC(F)=C(N=C12)C1=C(O)C=CC=C1F

References

General References
  1. Authors unspecified: AMG 510 First to Inhibit "Undruggable" KRAS. Cancer Discov. 2019 Aug;9(8):988-989. doi: 10.1158/2159-8290.CD-NB2019-073. Epub 2019 Jun 12. [PubMed:31189530]
  2. Fiala O, Pesek M, Finek J, Benesova L, Belsanova B, Minarik M: The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Cancer Genet. 2013 Jan-Feb;206(1-2):26-31. doi: 10.1016/j.cancergen.2012.12.003. Epub 2013 Jan 10. [PubMed:23313110]
  3. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter JD, Volak LP, Houk BE, Fakih MG, O'Neil BH, Price TJ, Falchook GS, Desai J, Kuo J, Govindan R, Hong DS, Ouyang W, Henary H, Arvedson T, Cee VJ, Lipford JR: The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 Oct 30. pii: 10.1038/s41586-019-1694-1. doi: 10.1038/s41586-019-1694-1. [PubMed:31666701]
  4. Christensen JG, Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, Sudhakar N, Bowcut V, Baer BR, Ballard JA, Burkard MR, Fell JB, Fischer JP, Vigers GP, Xue JY, Gatto S, Fernandez-Banet J, Pavlicek A, Velastegui K, Chao RC, Barton J, Pierobon M, Baldelli E, Patricoin EF, Cassidy DP, Marx MA, Rybkin II, Johnson ML, Ou SI, Lito P, Papadopoulos KP, Janne PA, Olson P: The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2019 Oct 28. pii: 2159-8290.CD-19-1167. doi: 10.1158/2159-8290.CD-19-1167. [PubMed:31658955]
ChemSpider
72380148
Wikipedia
AMG_510

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentKRAS p, G12c Mutated /Advanced Metastatic NSCLC1
2Not Yet RecruitingTreatmentAdenocarcinoma of the Lung / Non-Small Cell Lung Carcinoma (NSCLC) / Recurrent Lung Non-Squamous Non-Small Cell Carcinoma / Stage IV Lung Cancer AJCC v8 / Stage IVA Lung Cancer AJCC v8 / Stage IVB Lung Cancer AJCC v81
1RecruitingTreatmentAdvanced/Metastatic Solid Tumors With KRAS p.G12C Mutation1
1, 2RecruitingTreatmentKRAS p.G12C Mutant Advanced Solid Tumors1
Not AvailableAvailableNot AvailableLocally Advanced Metastatic NSCLC / Locally Advanced Unresectable NSCLC / Non-Small Cell Lung Carcinoma (NSCLC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0185 mg/mLALOGPS
logP3.6ALOGPS
logP4.74ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)6.98ChemAxon
pKa (Strongest Basic)4.74ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area102.23 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity150.12 m3·mol-1ChemAxon
Polarizability57.21 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein complex binding
Specific Function
Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Plays an important role in the regulation of cell proliferation (PubMed:23698361, PubMed:22711838).
Gene Name
KRAS
Uniprot ID
P01116
Uniprot Name
GTPase KRas
Molecular Weight
21655.67 Da
References
  1. Authors unspecified: AMG 510 First to Inhibit "Undruggable" KRAS. Cancer Discov. 2019 Aug;9(8):988-989. doi: 10.1158/2159-8290.CD-NB2019-073. Epub 2019 Jun 12. [PubMed:31189530]
  2. Fiala O, Pesek M, Finek J, Benesova L, Belsanova B, Minarik M: The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Cancer Genet. 2013 Jan-Feb;206(1-2):26-31. doi: 10.1016/j.cancergen.2012.12.003. Epub 2013 Jan 10. [PubMed:23313110]
  3. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter JD, Volak LP, Houk BE, Fakih MG, O'Neil BH, Price TJ, Falchook GS, Desai J, Kuo J, Govindan R, Hong DS, Ouyang W, Henary H, Arvedson T, Cee VJ, Lipford JR: The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 Oct 30. pii: 10.1038/s41586-019-1694-1. doi: 10.1038/s41586-019-1694-1. [PubMed:31666701]

Drug created on November 01, 2019 18:34 / Updated on June 12, 2020 16:53