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 <b>7g</b>, <b>7p</b>, <b>7q</b>, <b>7r</b>, <b>7v</b>, and <b>7y</b> 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, <b>7q</b> (MH5) exhibited satisfactory cellular selectivity, moderate pharmacokinetic characters, and good anticancer effects on pancreatic, colorectal cancer xenograft in vivo. Meaningfully, <b>7q</b> combined with Nrf2 inhibitor ML385 or PARP7 inhibitor RBN-2397 greatly enhanced the sensitivity of <b>7q</b> against lung cells (H1373) in vivo. Furthermore, combination therapy of <b>7q</b> 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 <b>7q</b> 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.