What question did this study set out to answer?

The aim is to design KRAS G12C inhibitors and assess their effectiveness when combined with Nrf2 and PARP-7 inhibitors.

February 6, 2026

Design and Synthesis of KRAS G12C Inhibitors for Antitumor Evaluation Harboring Combination Therapy with Nrf2, PARP-7, and Pan-USP Inhibitors to Alleviate Drug Resistance Synergistically

Key Points

The aim is to design KRAS G12C inhibitors and assess their effectiveness when combined with Nrf2 and PARP-7 inhibitors.
Synthesis of KRAS G12C inhibitors
Assessment of antiproliferative activity against H358 cells
Evaluation of combination therapies in vitro and in vivo
In vivo testing on pancreatic and colorectal cancer xenografts
Compound 7q (MH5) showed strong antiproliferative effects with IC50 values < 1 nM
7q combined with Nrf2 and PARP7 inhibitors increased its effectiveness against lung cancer cells
Combination with pan-USP inhibitor PR-619 led to significant growth inhibition in H1373 cells

Abstract

Compared with positive control MRTX849, the synthesized compounds 7g, 7p, 7q, 7r, 7v, and 7y displayed stronger antiproliferative activities against H358 cells with IC50 values of G12C. Among them, 7q (MH5) exhibited satisfactory cellular selectivity, moderate pharmacokinetic characters, and good anticancer effects on pancreatic, colorectal cancer xenograft in vivo. Meaningfully, 7q combined with Nrf2 inhibitor ML385 or PARP7 inhibitor RBN-2397 greatly enhanced the sensitivity of 7q against lung cells (H1373) in vivo. Furthermore, combination therapy of 7q with pan-USP inhibitor PR-619 obtained a statistically significant synergistic inhibition of H1373 cell growth in vitro and in vivo. Our findings indicate that 7q may be a promising drug candidate for the treatment of cancers harboring the KRASG12C mutation, and the results of the combination regimen established a pharmacological foundation for addressing drug resistance.

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