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ACS Med Chem Lett. 2017 Sep 7;8(10):1093-1098. doi: 10.1021/acsmedchemlett.7b00296. eCollection 2017.

From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome.

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  • 1Refractory Respiratory Inflammation DPU, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
  • 2Molecular Discovery Research, Biological Sciences, and Computational Chemistry, Platform Technology & Science, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.


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.


PI3Kδ inhibitor; Phosphoinositide-3-kinase delta inhibitor; kinase cross-screening

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