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Development of PI3Kγ selective inhibitors: the strategies and application

Acta Pharmacologica Sinica volume 45, pages 238–247 (2024)Cite this article

Abstract

The γ isoform of Class I PI3Ks (PI3Kγ) is primarily found in leukocytes and is essential for the function of myeloid cells, as it regulates the migration, differentiation, and activation of myeloid-lineage immune cells. Thus, PI3Kγ has been identified as a promising drug target for the treatment of inflammation, autoimmune disease, and immuno-oncology. Due to the high incidence of serious adverse events (AEs) associated with PI3K inhibitors, in the development of PI3Kγ inhibitors, isoform selectivity was deemed crucial. In this review, an overview of the development of PI3Kγ selective inhibitors in the past years is provided. The isoform selectivity of related drugs was achieved by different strategies, including inducing a specificity pocket by a propeller-shape structure, targeting steric differences in the solvent channel, and modulating the conformation of the Asp-Phe-Gly DFG motif, which have been demonstrated feasible by several successful cases. The insights in this manuscript may provide a potential direction for rational drug design and accelerate the discovery of PI3Kγ selective inhibitors.

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Fig. 1: The structural biology of PI3Kγ.
Fig. 2
Fig. 3: IPI-549 (5), the first PI3Kγ-selective inhibitor developed by Infinity Pharmaceuticals.
Fig. 4
Fig. 5: The comparison between the binding modes of PIK-93 and compound 6.
Fig. 6: X-ray structure of compound 7 bound to PI3Kγ (PDB: 4PS3).
Fig. 7
Fig. 8
Fig. 9: Docking model for compound 9 bound to PI3Kγ.
Fig. 10
Fig. 11: Mechanistic hypothesis for PI3Kγ isoform selectivity of AZ series compounds.
Fig. 12
Fig. 13

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Funding

This work was supported by the National Natural Science Foundation of China (82003780).

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Authors and Affiliations

  1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Dong-yan Gu & Rong Sheng

  2. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Meng-meng Zhang, Jia Li & Yu-bo Zhou

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Correspondence to Rong Sheng.

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Gu, Dy., Zhang, Mm., Li, J. et al. Development of PI3Kγ selective inhibitors: the strategies and application. Acta Pharmacol Sin 45, 238–247 (2024). https://doi.org/10.1038/s41401-023-01166-8

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