Selective inhibitors of phosphoinositide 3-kinase delta are of interest for the treatment of inflammatory diseases. Initial optimization of a 3-substituted indazole hit compound targeting the kinase PIM1 focused on improving selectivity over GSK3β through consideration of differences in the ATP binding pockets. Continued kinase cross-screening showed PI3Kδ activity in a series of 4,6-disubstituted indazole compounds, and subsequent structure–activity relationship exploration led to the discovery of an indole-containing lead compound as a potent PI3Kδ inhibitor with selectivity over the other PI3K isoforms.

中文翻译：

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通过GSK3β从PIM1到PI3Kδ：通过Kinome进行目标跳跃

磷酸肌醇3-激酶δ的选择性抑制剂对于治疗炎性疾病是令人感兴趣的。针对激酶PIM1的3-取代的吲唑命中化合物的初始优化着重于通过考虑ATP结合口袋的差异来提高对GSK3β的选择性。持续的激酶交叉筛选显示了一系列4,6-二取代的吲唑化合物中的PI3Kδ活性，随后的结构-活性关系探索导致发现了作为有效PI3Kδ抑制剂的含吲哚的铅化合物，对其他PI3K同工型具有选择性。