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

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 < 1 nM (3D cell culture) and comparable inhibitory potency against KRAS^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 KRAS^G12C mutation, and the results of the combination regimen established a pharmacological foundation for addressing drug resistance.