Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL)

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.

鉴于其在细胞增殖过程中的关键作用，微管相关丝氨酸/苏氨酸激酶样蛋白（MASTL）是一种全新的药物靶点，同时具备首创新药（FIC）的开发潜力，可为肿瘤患者带来极具临床价值的治疗手段。本文报道了一项从苗头化合物到先导化合物的优化研究，最终获得了两款高选择性MASTL抑制剂。本研究采用的核心策略包括基于结构的药物设计（SBDD）、亲脂效率（LipE）分析以及全新的合成路线开发。所获得的优质先导化合物支持了肿瘤生长抑制实验，该实验对于评估MASTL作为肿瘤治疗靶点的潜在价值具有关键意义。