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Henley ZA, Bax BD, Inglesby LM, et al. From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome. ACS Med Chem Lett. 2017;8(10):1093-1098doi: 10.1021/acsmedchemlett.7b00296.
Henley, Z. A., Bax, B. D., Inglesby, L. M., Champigny, A., Gaines, S., Faulder, P., Le, J., Thomas, D. A., Washio, Y., & Baldwin, I. R. (2017). From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome. ACS medicinal chemistry letters, 8(10), 1093-1098. https://doi.org/10.1021/acsmedchemlett.7b00296
Henley, Zoë A, et al. "From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome." ACS medicinal chemistry letters vol. 8,10 (2017): 1093-1098. doi: https://doi.org/10.1021/acsmedchemlett.7b00296
Henley ZA, Bax BD, Inglesby LM, Champigny A, Gaines S, Faulder P, Le J, Thomas DA, Washio Y, Baldwin IR. From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome. ACS Med Chem Lett. 2017 Sep 07;8(10):1093-1098. doi: 10.1021/acsmedchemlett.7b00296. eCollection 2017 Oct 12. PMID: 29057057; PMCID: PMC5642016.
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ACS Med Chem Lett. 2017 Sep 07;8(10):1093-1098. doi: 10.1021/acsmedchemlett.7b00296. eCollection 2017 Oct 12.

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

ACS medicinal chemistry letters

Zoë A Henley, Benjamin D Bax, Laura M Inglesby, Aurélie Champigny, Simon Gaines, Paul Faulder, Joelle Le, Daniel A Thomas, Yoshiaki Washio, Ian R Baldwin

Affiliations

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

PMID: 29057057 PMCID: PMC5642016 DOI: 10.1021/acsmedchemlett.7b00296

Abstract

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.

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

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