PF-07328948 is the first potent, selective branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK) with in vitro IC50 of 15 nM, and cellular IC50 of 46 nM in human skeletal muscle BDK activity assay.
PF-07328948 is not only a BDK inhibitor but also BDK degrader.
PF-07328948 shows a high degree of selectivity over a number of enzymes, receptors, and ion channels, as well as excellent kinase selectivity.
PF-07328948 binds to the BDK allosteric pocket and does not contain a traditional ATP-binding site motif.
PF-07328948 binds to BDK with SPR Kd of 4.8 nM.
PF-07328948 also destabilizes the interaction between BDK and E2.
PF-07328948 also shows high species potency against mouse BDK IC50 = 41 nM, rat BDK IC50 = 24 nM, and dog BDK IC50 = 24 nM. lowered plasma biomarkers, including BCAAs and branched-chain ketoacids (BCKAs) in vivo with enhanced pharmacodynamic effect upon chronic dosing due to BDK degradation.