Abstract 388: HZ-V068, an oral, highly potent pan-Ras molecular glue inhibitor demonstrated robust potency in pancreatic ductal adenocarcinoma and colorectal cancer models

Abstract Introduction: Ras oncogenes are frequently mutated in approximately 30% of all human cancers, which drive tumor growth and metastasis. The current approved Kras-targeted drugs are Kras G12C inhibitors. However, Kras G12C is only prevalent in part of lung cancer. Most of common mutations in pancreatic ductal adenocarcinoma (PDAC) or colorectal cancers (CRC) including Kras G12D, G12V, G12R are still lack of approved drugs. RMC6236, a next generation of novel pan-RasMulti(on) inhibitor which functions as molecular glue to form binary complex with CYPA and RasMulti and sterically blocks Ras binding to effectors, has been validated as a superior strategy targeting Ras in clinical study. Given GTP-bound RAS proteins as a promising new approach to enhance clinical benefits, we have developed a novel oral available pan-Ras molecular glue——HZ-V068 based on in-house Rational Molecular Glue Design Platform, which exhibits significantly binding affinity to CYPA, enriched tumor exposure and prolonged Ras inhibition. HZ-V068 has been validated as a promising pre-clinical candidate for further clinical development. Results: 1. In biochemical assays, HZ-V068 more potently disrupted the binding of KRASMut(On) to BRAF in a CypA-dependent manner. 2. HZ-V068 suppressed the growth of KrasMulti-BaF3 cell-line covering various mutation types (G12C/D/V/R, G13C/D, Q61K, A146V) at picomolar level. Moreover, HZ-V068 demonstrated 5-10 folds stronger potency in KrasMulti-addicted cancer cell lines compared to RMC-6236. 3. In a single-dose PK/PD study, HZ-V068 demonstrated rapid and more sustained intratumoral pERK inhibition, improved bioavailability, and enhanced tumor distribution. 4. In multiple KrasMulti-driven PDAC or CRC CDX models, oral administration of HZ-V068 results in robust tumor regression at lower doses, demonstrating efficacy that is significantly superior to that of RMC6236 Conclusion: In summary, HZ-V068 is a promising targeted therapeutic option for PDAC and CRC. Based on these promising results, we are advancing HZ-V068 into clinical study. Citation Format: Yizhe Wu, Jiangfeng Xie, Jinglai Huang, Xinglu Zhou. HZ-V068, an oral, highly potent pan-Ras molecular glue inhibitor demonstrated robust potency in pancreatic ductal adenocarcinoma and colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 388.