Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose

Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]­hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.果糖摄入增加及其后续代谢过程，与非酒精性脂肪性肝病及非酒精性脂肪性肝炎（nonalcoholic fatty liver disease and steatohepatitis, NAFLD/NASH）、胰岛素抵抗等代谢紊乱密切相关。己酮糖激酶（Ketohexokinase, KHK）是代谢级联反应的首个关键酶，可将果糖转化为1-磷酸果糖（fructose-1-phosphate, F1P）。本文报道了一款首创类KHK抑制剂PF-06835919（8）的发现历程，该化合物目前已进入II期临床试验。先导化合物8的研发基于本团队最初报道的片段衍生先导物1，且得益于一项关键结合模式发现：当核糖口袋结合基团从吡咯烷基环系替换为氮杂环丁基环系时，配体呈现出全新的翻转结合模式。这种新型结合模式使得研究团队能够有效探索针对精氨酸108（Arg-108）残基的作用向量，最终结合平行药物化学（parallel medicinal chemistry）与基于结构的药物设计（structure-based drug design）手段，成功发现了活性极高的3-氮杂双环[3.1.0]己烷乙酸类KHK抑制剂。