Design, Synthesis, Anticancer Evaluation and Molecular Docking of Pyrimidine, Pyrido[4,3-d]pyrimidine and 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidine Derivatives as Novel KRAS-G12D Inhibitors and PROTACs.

ABSTRACT: Background: KRAS-G12D mutations drive 20-50% of pancreatic/biliary cancers yet remain challenging to target due to GTP-pocket conservation and high cellular GTP levels. While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular/enzymatic activity relationships necessitate the exploration of novel scaffolds. This study aims to develop KRAS-G12D inhibitors and PROTACs to offer a selection of new chemical entities through systematic structure-activity optimization and evaluate their therapeutic potential through PROTAC derivatization. Methods: Eleven compounds featuring heterocyclic cores (pyrimidine/pyrido[4,3-d]pyrimidine/5,6,7,8-tetrahydroprodo[3,4-d]pyrimidine) were designed via structure-based dru

SUBMITTER: Yang H 

PROVIDER: S-EPMC12114952 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature