申请人:Arvinas Operations, Inc.
公开号:US11161841B2
公开(公告)日:2021-11-02
The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
本公开涉及双功能化合物,它们可用作 Kirsten 大鼠肉瘤蛋白(靶蛋白)的调节剂。特别是,本公开涉及双功能化合物,其一端含有与相应 E3 泛素连接酶结合的 Von Hippel-Lindau、cereblon、Apotosis Proteins 抑制剂或小鼠双敏同源物 2 配体,另一端含有与靶蛋白结合的分子,从而使靶蛋白靠近泛素连接酶以实现对靶蛋白的降解(和抑制)。本公开物具有与降解/抑制靶蛋白相关的广泛药理活性。本公开的化合物和组合物可以治疗或预防因目标蛋白的聚集、积累和/或过度激活而导致的疾病或失调。