Background: HBW-012-E is a newly identified KRAS G12D small molecule inhibitor with improved oral bioavailability than MRTX1133, the more advanced clinical candidate with poor bioavailability. Methods: Small molecules were designed through our medicinal chemistry efforts, aiming to discover KRAS G12D inhibitors that are of good oral bioavailability. The compounds were screened via pERK and cell viability (CTG) assays in multiple cell types. The optimized compounds were further evaluated based on their PK properties and toxicity. The anti-tumor efficacy of the leads was confirmed in a mouse GP2D (with KRAS G12D) colon cancer model. Results: As shown in the table, HBW-012-E has better potency and PK characteristics than MRTX1133. In the GP2D model, comparing head-to-head with the same vehicle and protocol (50 mg/kg, BID, PO), HBW-012-E can not only inhibit tumor growth completely but also further regress tumor size by ~40%, whereas MRTX1133 can hardly inhibit tumor growth. HBW-012-E demonstrated anti-tumor efficacy in a dose-dependent manner; at a dose as low as 10 mg/kg, it achieved ~80 % tumor inhibition rate (TGI). Preliminary toxicity tests showed that HBW-012-E is 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. Conclusions: A new KRAS G12D inhibitor, HBW-012-E, was identified. Its preclinical profile, including potency, efficacy, and PK properties, are all superior to MRTX1133, and its safety meets the criteria of clinical development. It can potentially be used to treat intractable tumors mediated by KRAS G12D mutations, such as pancreatic cancer that still lacks effective treatments.