Abstract LB345: HZ-V055, an oral, highly potent pan-Ras molecular glue inhibitor demonstrated robust potency in RasMut 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. RMC-6236, a novel pan-RasMut(on) inhibitor which functions as molecular glue to form ternary complex with CYPA and RasMut and sterically blocks Ras binding to effectors, has been validated as a superior strategy targeting Ras in clinical study. RMC-6236 has achieved satisfied efficacy in Ras mutated patients. However, the high incidence of GI or skin relevant AE is still a great concern of Pan-Ras molecular glue. Concurrently inhibition of RasMut and RasWT is proposed as the main reason to cause these AEs. To address this issue, a next generation of selective pan-Ras molecular glue HZ-V055 was carried out through Healzen’s in-house Rational Molecular Glue Design Platform. HZ-V055 has been validated as a promising pre-clinical candidate with improved selectivity between RasWT and Kras G12C/D/V. Results: 1. HZ-V055 more potently disrupted the complex formation of mutant Kras (KrasMut, active state) and BRAF in a cyclophilin A (CypA)-dependent manner. Moreover, HZ-V055 exhibited 4-11-fold higher selectivity for KrasG12C/D/V mutants over wild-type (wt) Ras, compared with RMC-6236. 2. HZ-V055 demonstrated 5-10-fold stronger antiproliferative potency in RasMut-addicted cancer cell lines relative to RMC-6236. In contrast, HZ-V055 showed almost no antiproliferative activity against non-malignant cells or Ras-independent cancer cell lines. 3. In multiple CDX models of pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer (CRC) driven by KrasMut, oral administration of HZ-V055 induced robust tumor regression at a low dose of 0.04 mg/kg, representing a 25-50-fold efficacy enhancement over RMC-6236. 4. At efficacious doses that induce tumor regression against most G12C/D/V CDX models, both HZ-V055(at 1X dose) and RMC-6236( at 25X dose) comparably suppressed DUSP6 expression, which is a biomarker of Ras pathway activation, in tumor tissues. Furthermore, the inhibitory effect of DUSP6 in mouse ear skin tissue was also evaluated to investigate the suppression of Ras(WT). The results demonstrated that at efficacious doses HZ-V055 exhibits significantly weaker Ras(WT) inhibition than that of RMC-6236. 5. A comparative analysis of the therapeutic window was also performed between HZ-V055 and RMC-6236. In KrasG12C/D/V-driven tumor models, HZ-V055 exhibited a 3-fold wider therapeutic window than RMC-6236. Conclusion: In summary, HZ-V055 is an orally available, selective pan-Ras molecular glue inhibitor. In preclinical models, its enhanced selectivity for KrasG12C/D/V mutants over wild-type (wt) K/H/N-Ras confers two key advantages over RMC-6236: reduced Ras(WT) pathway inhibition in skin tissues and a significantly expanded therapeutic window. Collectively, these preclinical findings validate HZ-V055 as a highly promising candidate for further clinical development. Currently, HZ-V055 is in the IND-enabling stage, with a Phase I clinical trial slated to initiate in the second half of 2026 (H2 2026). Citation Format: Yizhe Wu, Bo Feng, Jiangfeng Xie, Peipei Wang, Jinglai Huang, Xiaobei Hu, Gaoya Xu, Yubo Zhou, Jia Li, Xinglu Zhou. HZ-V055, an oral, highly potent pan-Ras molecular glue inhibitor demonstrated robust potency in RasMut cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB345.