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PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond

Lookup NU author(s): Professor Andrew Cant

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2023 The Authors. The phosphoinositide 3-kinase (PI3K) pathway regulates diverse cellular processes, with finely tuned PI3Kδ activity being crucial for immune cell development and function. Genetic hyperactivation of PI3Kδ causes the inborn error of immunity activated phosphoinositide 3-kinase δ syndrome (APDS). Several PI3Kδ inhibitors have been investigated as treatment options for APDS, but only leniolisib has shown both efficacy and tolerability. In contrast, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematological malignancies. We propose that leniolisib is distinguished from other PI3Kδ inhibitors due to its structure, specific inhibitory properties selectively targeting the δ isoform without overinhibition of the δ or γ isoforms, and the precise match between APDS mechanism of disease and drug mechanism of action.

Publication metadata

Author(s): Cant AJ, Chandra A, Munro E, Rao VK, Lucas CL

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology: In Practice

Year: 2024

Volume: 12

Issue: 1

Pages: 69-78

Print publication date: 01/01/2024

Online publication date: 28/09/2023

Acceptance date: 11/09/2023

Date deposited: 06/11/2023

ISSN (print): 2213-2198

ISSN (electronic): 2213-2201

Publisher: Elsevier BV

URL: https://doi.org/10.1016/j.jaip.2023.09.016

DOI: 10.1016/j.jaip.2023.09.016

PubMed id: 37777067

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