Adagrasib

MRTX849 is a potent, selective and covalent KRASG12C inhibitor with potential antineoplastic activity. It selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling.

Sotorasib is the first FDA-approved inhibitor for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). Subsequently, the FDA granted Breakthrough Therapy designation to Adagrasib, providing a potential treatment option for patients with KRASG12C-mutated NSCLC who have previously undergone systemic therapy. KRASG12C is a specific submutation of KRAS, constituting approximately 44% of all KRAS mutations. It is most commonly found in adenocarcinomas of non-small cell lung cancer, followed by colorectal adenocarcinomas and pancreatic cancers. Globally, over 100,000 people are diagnosed with KRASG12C mutations annually. Sotorasib represents a novel discovery in cancer treatment. Preclinical and clinical studies indicate that cellular differentiation, molecular activation, and genetic mutations can contribute to intrinsic or acquired resistance to KRASG12C inhibitors, including ARS-1620, sotorasib, and adagrasib.

2326521-71-3

AMG-510 is a selective and orally bioavailable KRAS G12C covalent inhibitor.

C32H35ClFN7O2

Sotorasib and Adagrasib are selective KRASG12C inhibitors. The KRAS protein is a signaling GTPase that can switch between an active GTP-bound conformation and an inactive GDP-bound conformation. KRASG12C is a specific submutation of KRAS, where glycine at the 12th codon is replaced by cysteine. Both Sotorasib and Adagrasib covalently bind to the cysteine residue in the KRASG12C mutant, locking the KRAS protein in an inactive state. This disruption of downstream signaling pathways contributes to the anti-tumor effects, without affecting the wild-type KRAS. KRAS can hydrolyze the γ-phosphate of GTP to convert it to GDP. The inactive and active states of KRAS are regulated by GAP and GEF, respectively. RTKs (Receptor Tyrosine Kinases) represent the second-largest class of cell surface receptors with diverse functions, including the promotion of KRAS activation and subsequent involvement in various downstream pathways, notably the RAF-MEK-ERK and PI3K-AKT-mTOR pathways. Unlike wild-type KRAS, which maintains a balance between inactive and activated states, the cysteine 12 (C12) mutation disrupts the GTPase activity of KRAS, locking it in the GTP-bound state. In contrast, small molecule drugs like sotorasib (or adagrasib) can form a covalent bond with the C12 residue in the KRAS-G12C protein, resulting in KRAS being in an inactive state.

604.13

GPCR/G Protein; MAPK

0.999

NSCLC (Non-small-cell lung cancer); Adenocarcinoma; Rectal adenocarcinoma; Pancreatic cancer

CN1CCC[C@H]1COc1nc2CN(CCc2c(n1)N1CCN([C@@H](CC#N)C1)C(=O)C(F)=C)c1cccc2cccc(Cl)c12

Ras