Sotorasib

Sotorasib (pINN), codenamed AMG 510, is an experimental cancer drug. It targets a specific mutation, G12C, in the protein KRAS which is responsible for various forms of cancer.[1][2]

Sotorasib
Identifiers
IUPAC name
  • 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC30H30F2N6O3
Molar mass560.606 g·mol−1
3D model (JSmol)
SMILES
  • CC(C)c1nccc(C)c1N2C(=O)N=C(N3CCN(C[C@@H]3C)C(=O)C=C)c4cc(F)c(nc24)c5c(O)cccc5F
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
  • Key:NXQKSXLFSAEQCZ-SFHVURJKSA-N

Clinical development

Sotorasib is being developed by Amgen. Phase 1 clinical trials were completed in late 2020.[3][4][5] In December 2019, it was approved to begin Phase 2 clinical trials.[6]

Because the G12C KRAS mutation is relatively common in some cancer types, 14% of non-small-cell lung cancer adenocarcinoma patients and 5% of colorectal cancer patients,[7] and sotorasib is the first drug candidate to target this mutation, there have been high expectations for the drug.[7][8][9] The Food and Drug Administration has granted a fast track designation to sotorasib for the treatment of metastatic non-small-cell lung carcinoma with the G12C KRAS mutation.[10]

Chemistry and pharmacology

Sotorasib can exist in either of two atropisomeric forms and one is more active than the other.[7] It selectively forms an irreversible covalent bond to the sulfur atom in the cysteine residue that is present in the mutated form of KRAS, but not in the normal form.[7]

See also
  • Adagrasib

References
  1. "KRAS mutant-targeting AMG 510". NCI Drug Dictionary. National Cancer Institute. 2011-02-02. Retrieved November 16, 2019.
  2. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. (November 2019). "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity". Nature. 575 (7781): 217–223. Bibcode:2019Natur.575..217C. doi:10.1038/s41586-019-1694-1. PMID 31666701.
  3. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. (2020). "KRASG12C inhibition with sotorasib in advanced solid tumors". N Engl J Med. doi:10.1056/NEJMoa1917239. PMC 7571518.
  4. Clinical trial number NCT03600883 for "A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation " at ClinicalTrials.gov
  5. "The Discovery Of Amgen's Novel Investigational KRAS(G12C) Inhibitor AMG 510 Published In Nature" (Press release). Amgen. October 30, 2019. Retrieved November 16, 2019.
  6. Irving M (2019-12-24). "Drug targeting common cancer cause enters phase 2 clinical trials". New Atlas. Retrieved 2019-12-24.
  7. Halford B (April 3, 2019). "Amgen unveils its KRas inhibitor in human clinical trials: AMG 510 shuts down a mutant version of the cancer target via covalent interaction". Chemical & Engineering News. 97 (4). Retrieved November 16, 2019.
  8. Al Idrus A (September 9, 2019). "Amgen's KRAS drug continues to deliver but faces 'curse' of high expectations". fiercebiotech.com. Retrieved November 16, 2019.
  9. Kaiser J (2019-10-30). "Two new drugs finally hit 'undruggable' cancer target, providing hope for treatments". Science Magazine. AAAS. Retrieved November 16, 2019.
  10. Astor L (September 9, 2019). "FDA Grants AMG 510 Fast Track Designation for KRAS G12C+ NSCLC". targetedonc.com. Retrieved November 16, 2019.
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