Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States.
Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE 19803, United States.
Bioorg Med Chem Lett. 2022 Jan 1;55:128452. doi: 10.1016/j.bmcl.2021.128452. Epub 2021 Nov 13.
Activin receptor-like kinase 2 (ALK2) has been implicated as a key target in multiple rare diseases. Herein, we describe the design of a novel bicyclic lactam series of potent and selective ALK2 inhibitors. This manuscript details an improvement in potency of two orders of magnitude from the initial bicyclic structure as well as a two-fold improvement in cellular potency from the original monocyclic inhibitor. Furthermore, we provide a detailed strategy for progressing this project in the future.
激活素受体样激酶 2（ALK2）已被认为是多种罕见疾病的关键靶点。本文描述了一类新型双环内酰胺类强效和选择性 ALK2 抑制剂的设计。本手稿详细介绍了从初始双环结构提高两个数量级的效力，以及从原始单环抑制剂提高两倍的细胞效力的改进。此外，我们还提供了一个详细的策略，用于未来推进该项目。
