PF-07238025, a potent branched-chain ketoacid dehydrogenase kinase (BDK) inhibitor with an EC50 of 19 nM, enhances the stability of the BDK-BCKDH core E2 subunit interaction and inhibits the phosphorylation of the E1 subunit. By modulating BDK, which regulates the phosphorylation of BCKDH, a key enzyme in branched-chain amino acid (BCAA) degradation, PF-07238025 indirectly controls the rate-limiting step in BCAA catabolism. Dysregulated BCAA metabolism is implicated in various cardiometabolic disorders such as heart failure (HF), type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and obesity. Notably, PF-07238025 has been shown to ameliorate cardiometabolic endpoints and enhance glucose tolerance in mouse models [1].

PF-07238025 (0.2-6 μM；48小时) 在Hek293细胞中呈剂量依赖性降低pBCKDH，同时导致BDK积累提升50% [1]。

PF-07238025（20 mg/kg、100 mg/kg；8周）在高脂饮食（HFD）小鼠模型中给药后2天能有效降低血糖波动，并在第7天显著减少分枝链氨基酸（BCAA）和分枝链酮酸（BCKA）的水平[1]。