Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies. Plasma biomarkers, including BCAAs and branched-chain ketoacids (BCKAs), were lowered in vivo with enhanced pharmacodynamic effect upon chronic dosing due to BDK degradation. This molecule improves metabolic and heart failure end points in rodent models. PF-07328948 is the first known selective BDK inhibitor candidate to be examined in clinical studies, with Phase 1 single ascending dose data showing good tolerability and a pharmacokinetic profile commensurate with once-daily dosing.

中文翻译：

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第一个支链酮酸脱氢酶激酶 （BDK） 抑制剂临床候选物 PF-07328948 的发现


支链酮酸脱氢酶激酶 （BDK 或 BCKDK） 是支链氨基酸 （BCAA） 代谢的负调节因子，据推测可治疗心脏代谢疾病。从具有潜在特异质毒性风险的起点开始，对苯并噻吩核心的修饰和隐蔽口袋的发现允许通过 3-芳基取代提高效力，从而得到 PF-07328948，它基本上没有蛋白质共价结合倾向。该 BDK 抑制剂在细胞和体内啮齿动物研究中也被证明是一种 BDK 降解剂。由于 BDK 降解，包括 BCAA 和支链酮酸 （BCKA） 在内的血浆生物标志物在体内降低，在慢性给药后药效学作用增强。该分子可改善啮齿动物模型中的代谢和心力衰竭终点。PF-07328948 是第一个在临床研究中检查的已知选择性 BDK 抑制剂候选药物，1 期单次递增剂量数据显示良好的耐受性和与每日一次给药相称的药代动力学特征。