Pagba, C. V. | bioRxiv Science

bioRxiv2025

MRTX1133 is a potent non-covalent KRAS (G12C) inhibitor with tissue-specific activity

KRAS is a high-value therapeutic target for the treatment of cancer. Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), have received accelerated approvals for clinical use. Studies of these inhibitors ushered in the development of new inhibitors such as MRTX1133, that had entered clinical trials as a KRAS (G12D)-selective, non-covalent inhibitor. However, the subsequent failure of sotorasib as monotherapy and the recent termination of an early-phase clinical trial for MRTX1133 indicates that developing clinically effective allele-specific KRAS inhibitors remains a challenge, and that there is a need for further evaluation of KRAS inhibition mechanisms. Here, we show that the reportedly KRAS (G12D)-selective MRTX1133 also binds to G12C mutant KRAS with high affinity and suppresses MAPK signaling in cancer cell lines harboring KRAS (G12C). Intriguingly, its effect on the proliferation of KRAS (G12C) cancer cells is context-dependent; MRTX1133 robustly inhibits the proliferation of the pancreatic cancer cell line MIA PaCa-2 as well as the tumor growth of MIA PaCa-2 mouse xenografts, but it has little effect in lung cancer cells. These findings, together with similar other recent reports, question if allele-specific KRAS inhibitors are truly selective and highlight the need for strategies that take into account tissue and context-specific processes. Significance StatementMRTX1133 is a reportedly selective, non-covalent inhibitor for the KRAS oncogene with a glycine-to-aspartate (G12D) mutation that is present in about 40% of pancreatic cancers. Despite the overwhelming preclinical success, the early-phase clinical trial of MRTX1133 was recently terminated with undisclosed results. Through our in vitro and in vivo studies, we discovered that MRTX1133 is also a potent non-covalent inhibitor of a glycine-to-cysteine (G12C) KRAS mutation that works in pancreatic cancer but not in lung cancer models. Our findings are consistent with other recent reports on the activity of MRTX1133 in non-G12D mutants and highlight challenges in developing true allele-specific KRAS inhibitors via non-covalent mechanisms while also accounting for tissue-specific effects.

cancer biology↗

bioRxiv2018

Discovery of allosteric non-covalent KRAS inhibitors that bind with sub micromolar affinity and disrupt effector binding

Approximately 15% of all human tumors harbor mutant KRAS, a membrane-associated small GTPase and a notorious oncogene. Somatic mutations that render KRAS constitutively active lead to uncontrolled cell growth, survival, proliferation, and eventually cancer. KRAS is thus a critical anticancer drug target. However, despite aggressive efforts in recent years, there is no drug on the market that directly targets KRAS. In the current work, we combined molecular simulation and high-throughput virtual screening with a battery of cell-based and biophysical assays to discover a novel, pyrazolopyrimidine-based allosteric KRAS inhibitor that exhibits promising biochemical properties. The compound selectively binds to active KRAS with sub-micromolar affinity, slightly modulates exchange factor activity, disrupts effector Raf binding, significantly reduces signal transduction through mutant KRAS and inhibits cancer cell growth. Moreover, by studying two of its analogues, we identified key chemical features of the compound that are critical for affinity, effect on effector binding and mode of action. We propose a set of specific interactions with key residues at the switch regions of KRAS as critical for abrogating effector binding and reducing the rate of nucleotide exchange. Together, these findings not only demonstrate the viability of direct KRAS inhibition and offer guidance for future optimization efforts, but also show that pyrazolopyrimidine-based compounds may represent a first-in-class lead toward a clinically relevant targeting of KRAS by allosteric non-covalent inhibitors.

biochemistry↗