Discovery of\nFirst Branched-Chain Ketoacid Dehydrogenase\nKinase (BDK) Inhibitor Clinical Candidate PF-07328948

Inhibition of branched-chain ketoacid dehydrogenase kinase\n(BDK\nor BCKDK), a negative regulator of branched-chain amino acid (BCAA)\nmetabolism, is hypothesized to treat cardio-metabolic diseases. From\na starting point with potential idiosyncratic toxicity risk, modification\nto a benzothiophene core and discovery of a cryptic pocket allowed\nfor improved potency with 3-aryl substitution to arrive at PF-07328948,\nwhich was largely devoid of protein covalent binding liability. This\nBDK inhibitor was shown also to be a BDK degrader in cells and in\nvivo rodent studies. Plasma biomarkers, including BCAAs and branched-chain\nketoacids (BCKAs), were lowered in vivo with enhanced pharmacodynamic\neffect upon chronic dosing due to BDK degradation. This molecule improves\nmetabolic and heart failure end points in rodent models. PF-07328948\nis the first known selective BDK inhibitor candidate to be examined\nin clinical studies, with Phase 1 single ascending dose data showing\ngood tolerability and a pharmacokinetic profile commensurate with\nonce-daily dosing.