K-Ras(G12C) inhibitor 6

Last updated
K-Ras(G12C) inhibitor 6
K-Ras(G12C) inhibitor 6.svg
Names
Preferred IUPAC name
N-{1-[(2,4-Dichlorophenoxy)acetyl]piperidin-4-yl}-4-sulfanylbutanamide
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C17H22Cl2N2O3S/c18-12-3-4-15(14(19)10-12)24-11-17(23)21-7-5-13(6-8-21)20-16(22)2-1-9-25/h3-4,10,13,25H,1-2,5-9,11H2,(H,20,22)
    Key: ZPXCEHMKUTXHRZ-UHFFFAOYSA-N
  • SCCCC(=O)NC1CCN(CC1)C(=O)COC1=CC=C(Cl)C=C1Cl
Properties
C17H22Cl2N2O3S
Molar mass 405.33 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

K-Ras(G12C) inhibitor 6 is an irreversible inhibitor of oncogenic K-Ras(G12C), subverting the native nucleotide preference to favour GDP over GTP. Its family of inhibitors allosterically control GTP affinity and effector interactions by fitting inside a "pocket", or binding site, of mutant K-Ras. It is the most frequently mutated oncogene. [1]

Investigators and pathologists previously thought that K-Ras is undruggable. [2] However, Kevan M. Shokat and his colleagues, in the Howard Hughes Medical Institute (HHMI) at the University of California, recently reported a novel discovery of "Achilles heel" on K-Ras, and believed that it has real translational implications for patients with K-Ras mutation. [3] [4] [5] [6]

In recent years, significant research efforts have focused on finding effective inhibitors for the Kras-G12C mutation. For instance, sotorasib (Lumakras) became the first FDA-approved targeted therapy for the treatment of patients with NSCLC harboring the Kras-G12C mutation in 2021. [7] Adagrasib (MRTX849) is another inhibitor that has shown promising results in clinical trials. [8]

References

  1. ↑ "Targeting KRAS-G12C | Amgen Oncology". www.amgenoncology.com. Retrieved 2023-12-09.
  2. ↑ "Researchers identify new mechanism to target 'undruggable' cancer gene". www.sciencedaily.com. Retrieved 2017-01-17.
  3. ↑ Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013 Nov 28;503(7477):548-51. doi : 10.1038/nature12796 PMID   24256730
  4. ↑ Ostrem J, Shokat K. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov 2016; 15: 771–785. doi : 10.1038/nrd.2016.139
  5. ↑ Orgován Z, Keserű GM. Small molecule inhibitors of RAS proteins with oncogenic mutations. Cancer Metastasis Rev 2020; 39: 1107–1126. doi : 10.1007/s10555-020-09911-9
  6. ↑ Sabt A, Tawfik HO, Khaleel EF, Badi RM, Ibrahim HAA, Elkaeed EB, Eldehna WM. An overview of recent advancements in small molecules suppression of oncogenic signaling of K-RAS: an updated review. Mol Divers. 2024 Dec;28(6):4581-4608. doi : 10.1007/s11030-023-10777-6 PMID   38289431
  7. ↑ "Sotorasib is First KRAS Inhibitor Approved by FDA - NCI". www.cancer.gov. 2021-06-25. Retrieved 2023-12-09.
  8. ↑ Dhillon, Sohita (February 2023). "Adagrasib: First Approval". Drugs. 83 (3): 275–285. doi:10.1007/s40265-023-01839-y. ISSN   1179-1950. PMID   36763320.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.