一种新型高效的多重RAS抑制剂ZMS-2195在临床前模型中有效阻断MAPK通路激活并诱导强劲的抗肿瘤生长效应

Variants in the RAS family (HRAS, NRAS and KRAS) represent among the most prevalent oncogenic mutations identified in cancer. Approximately 19% of cancer patients harbor RAS mutations, which are typically associated with poor clinical outcomes. Multi-RAS inhibitor may overcome resistance by hitting a broader range of targets than single-mutant inhibitors. As such, multi-RAS inhibitors are anticipated to offer therapeutic potential across a wide range of RAS-driven malignancies. Here we report ZMS-2195, a novel and highly potent Multi-RAS inhibitor. Biochemical assays assessing disruption of the RAS-RAF complex demonstrated that ZMS-2195 effectively inhibited the interaction between multiple RAS variants-including KRAS, NRAS, and HRAS mutants and wild-type forms-and the RAF-RBD domain, with digital nanomolar IC 50 values. The cellular MAPK pathway inhibition was confirmed through robust suppression of phosphorylated ERK in representative cancer cell lines harboring diverse RAS mutant alleles. Consistent with the biochemical activity observed against multiple RAS variants and cellular pERK inhibition potency in RAS mutant cell lines, ZMS-2195 caused potent growth inhibition of KRAS mutant cancer cell lines, exemplified by Miapaca-2 (KRAS G12C/G12C , PDAC), AsPC-1(KRAS G12D/G12D , PDAC) and SW403 (KRAS G12V/WT , CRC) with IC 50 values of 0.8, 1.3 and 0.3 nmol/L, respectively. Wild-type RAS ( RAS WT ) cancer cells with GTP-activated RAS from upstream mutations were equally sensitive to ZMS-2195, exemplified by H1975(EGFR mut , NSCLC) with an IC 50 of 6.7 nmol/L. Conversely, RAS WT cancer cells harboring downstream BRAF mutations or RAS-independent normal cells were essentially insensitive to ZMS-2195. Favorable oral bioavailability and pharmacokinetic profiles were exhibited in pre-clinical species. Oral administration of ZMS-2195 resulted in dose-dependent and sustained suppression of RAS pathway signaling, as evidenced by reduced human DUSP6 mRNA expression levels in tumor lysates. Daily dosing of ZMS-2195 produced dose-dependent antitumor activity in xenograft models derived from RAS-driven human tumor xenograft model in vivo . At a dose of 0.8 mg/kg, ZMS-2195 induced tumor regression in PK59 (KRAS G12D/WT , PDAC) xenograft model. In summary, ZMS-2159 is a potent Multi-RAS inhibitor with robust activity against RAS-driven tumor cells, supporting its further development as a target therapy for cancers driven by diverse RAS aberrations.