Description
MRTX-849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favourable drug-like properties, modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signalling. MRTX-849 demonstrated pronounced tumour regression in 17 of 26 (65%) KRASG12C-positive cell line- and patient-derived xenograft models from multiple tumour types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas[1].
Uses
MRTX 849 is used as combination therapy for treatment of cancer.
General Description
Class: non-kinase;
Treatment: KRAS(G12C) NSCLC;
Other name: MRTX849;
Elimination half-life: 24 h;
Protein binding = 98.3%
Biological Activity
To minimize GSH metabolism, the development candidate MRTX-849 employed a 2-fluoroacrylamide warhead, imparting whole blood stability of >50 h t1/2 across species while maintaining tractable cellular potency (IC50 = 5–14 nM). Metabolism studies of MRTX-849 in hepatocytes showed that GSH conjugation of the 2-fluoroacrylamide was reduced compared to previous analogues containing the unsubstituted acrylamide. Favorable in vitro ADME and physical properties of MRTX-849 translated into moderate to high bioavailability of 26–63% across species tested. In a PK/PD experiment dosed at 10, 30, and 100 mg/kg to NCI-H358 tumor-bearing mice, MRTX-849 demonstrated dose-dependent protein modification with nearly maximal effect at the highest doses[2].
Mechanism of action
Adagrasib selectively modified mutant cysteine 12 in GDP-bound G12C and inhibited KRASdependent signaling.
Clinical Use
Adagrasib is an irreversible inhibitor of the RAS GTPase family. It is approved by the FDA for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have been identified by testing as having a KRAS (G12C) mutation.
target
Primary target: KRAS(G12C)
References
[1] Jay B. Fell. “Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.” Journal of Medicinal Chemistry 63 13 (2020): 6679–6693.
[2] J. Christensen. “The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients.” Cancer discovery (2019).
