Abstract 7010: HDB-82: A promising PROTAC degrader for KRAS G12D mutant cancers

Abstract KRAS G12D mutations, occurring in approximately 30% of solid tumors, represent a significant therapeutic target. While selective KRAS G12C inhibitors have achieved clinical success, effectively targeting the more prevalent G12D mutation remains an unmet medical need. This study investigates the potential of proteolysis-targeting chimeras (PROTACs) as a promising avenue for KRAS G12D-driven cancers, potentially offering advantages over traditional inhibitors through catalytic protein degradation. Targeted protein degradation of mutant KRAS may yield greater efficacy than simply inhibiting the protein. This study focuses on the design, synthesis, and biological evaluation of novel KRAS G12D-targeting PROTAC degraders. Through rigorous optimization, we developed HDB-82, a highly potent and selective PROTAC compound targeting KRAS G12D. HDB-82 effectively induced degradation of the KRAS G12D protein, leading to significant antiproliferative activity against KRAS G12D-mutant cancer cells in vitro and in vivo. HDB-82 demonstrated potent anti-cancer activity against various KRAS G12D-mutant cell lines, achieving low nanomolar IC50 values. It effectively degraded the KRAS G12D protein in various KRAS G12D-expressing cell lines (DC50 value ranges from picomolar to sub-nanomolar range). Mechanistic studies revealed significant suppression of downstream MAPK and PI3K/AKT signaling pathways, accompanied by robust induction of apoptosis, and superior antiproliferative activity compared to existing inhibitors. Furthermore, HDB-82 exhibited favorable pharmacokinetic and pharmacodynamic properties in mice. Intravenous administration of HDB-82 (10 mg/kg, q.w.) resulted in substantial tumor growth inhibition across multiple KRAS G12D-positive tumor models. These findings establish HDB-82 as a promising therapeutic candidate for KRAS G12D-mutant cancers, warranting further preclinical investigation and potential clinical development. Citation Format: Mohammad Hassan Baig, Yun Seong Jo, Sagar Dattatraya Nale, Chang Joong Kim, Tae Hwan Park, Ju Han Bok, Dong Min Kim, Hye Mi Kim, Ji Min Park, Jae June Dong, Jae Hee Cho, Sung Ill Jang, Byoung Gon Moon. HDB-82: A promising PROTAC degrader for KRAS G12D mutant cancers [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 7010.