Abstract 3325: HBW-012-D and HBW-012-E are novel, potent, selective, safe, and bioavailable KRAS G12D inhibitors with superior anti-tumor efficacy in mice

Abstract

Abstract Purpose: This study is to characterize newly identified KRAS G12D small molecule inhibitors HBW-012-D and HBW-012-E, both showing improved oral bioavailability than MRTX1133, the known clinical compound with poor bioavailability. Method: Through our medicinal chemistry efforts, we have aimed to design novel small-molecule KRAS G12D inhibitors that are orally bioavailable. The compounds were screened via pERK and cell viability (CTG) assays in multiple cell types. The optimized compounds were further evaluated based on their pharmacokinetic (PK) properties and toxicity. The anti-tumor efficacy of the leads was confirmed in the GP2D (colorectal carcinoma with KRAS G12D mutation) mouse xenograft tumor model. Result: As shown in the table, HBW-012-D and HBW-012-E have significantly better potency and PK characteristics than MRTX1133. In the mouse GP2D model, comparing head-to-head with the same vehicle and protocol (50 mg/kg, twice daily, orally), MRTX1133 hardly inhibited tumor growth, whereas HBW-012-D inhibited tumor growth well (58 % tumor growth inhibition), and HBW-012-E not only completely inhibited tumor growth but also further regressed tumor size by around 40%. Preliminary toxicity tests showed that HBW-012-D and HBW-012-E are safe: weak inhibition of CYP450 enzymes, negative mini-Ames test, excellent kinase selectivity, and no obvious abnormalities in the 14-day rat or mouse toxicity test. Conclusion: New KRAS G12D inhibitors, HBW-012-D and HBW-012-E, were identified. Their preclinical profile, including potency, efficacy, and PK data, are all superior to MRTX1133, and their safety meets the criteria of clinical development. They show potential as a preferred oral treatment option for patients with tumors mediated by the KRAS G12D mutation, such as pancreatic cancer that still lacks effective treatments. in vitro data IC 50 (nM) MRTX1133 HBW-012-D HBW-012-E AGS (G12D, stomach, pERK) 1 0.8 0.46 AsPC-1 (G12D, pancreas, 3D CTG) 10.88 3.09 GP2D (G12D, colon, 3D CTG) 1.38 0.67 0.69 MKN-1 (WT, stomach, 3D CTG) >3000 Rat PK @ 100 mg/kg oral Cmax (ng/mL) 9 82 1444 AUC0~t (mg.h/mL) 20 258 5724 Citation Format: Ning Lee, Yingfu Li, Guanfeng Liu, Jiang Li, Junfeng Ren. HBW-012-D and HBW-012-E are novel, potent, selective, safe, and bioavailable KRAS G12D inhibitors with superior anti-tumor efficacy in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3325.