PF-07238025 is a BCKDC kinase (BDK) inhibitor (EC50=19 nM). PF-07238025 stabilizes the interaction between BDK and BCKDH core subunit E2 and prevents phosphorylation of E1. While BDK mediates branched-chain ketoacid dehydrogenase (BCKDH) phosphorylation, and inhibition of BCKDH is involved in controlling the rate-limiting step of branched-chain amino acid (BCAA) degradation. Impaired BCAA catabolism has been associated with several diseases, particularly cardiometabolic diseases, including heart failure (HF), type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and obesity. PF-07238025 improved cardiometabolic endpoints and improves glucose tolerance in mice.
PF-07238025 (0.2-6 μM; 48 h) reduces pBCKDH in a dose-dependent manner in Hek293 cells, and increases BDK accumulation by 50%[1].
PF-07238025 (20 mg/kg, 100 mg/kg; 8 weeks) reduces glucose excursion after 2 days in HFD-fed mice, and leads significant reduction in both BCAAs and BCKAs by day 7[1].
References:
[1]. Roth Flach RJ, et al. Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels. Nat Commun. 2023 Aug 9;14(1):4812.