Therapeutic Potential of Phosphoinositide 3-Kinase δ-Selective Small Molecule Inhibitors

Kamal   D.   Puri

Abstract

The Class I phosphoinositide 3-kinase (PI3K) family of enzymes consists of four closely related isoforms (p110α, p110β, p110γ, and p110δ) that generate phospholipid second messengers and control pathways governing important cellular events such as migration, proliferation, apoptosis, neovascularization and metastasis. Recent findings suggesting involvement of these enzymes in the pathogenesis of numerous diseases have triggered considerable interest in the development of antagonists to class I PI3Ks as therapeutic agents. The two most widely used PI3K inhibitors, wortmannin and LY294002, do not distinguish adequately the activities of different PI3K isoforms and lack acceptable pharmacological and toxicological profiles. The fact that p110δ and p110γ expression is more restricted to cells of hematopoietic origin, in combination with recent genetic evidence, supports the hypothesis that selective inhibitors of these isoforms might exhibit more acceptable pharmacological and toxicological profiles. More recently several small molecule inhibitors, selective for the p110δ isoform, have been identified and evaluated in animal models of human disease. This review has summarized the current knowledge of the emerging therapeutic value of class I PI3Ks in general, and p110δ in particular, for the intervention in several pathological disorders. Herein, the phenotypic consequences of genetically targeting PI3K signaling in mice, identification and characterization of PI3K isoform selective inhibitors and their efficacy in animal models of human disease such as cancer, autoimmune/inflammatory disorders and allergic diseases have beeen discussed. Lastly, the challenges of considering PI3Ks as targets for therapeutic intervention has also been summarized.

Keywords: Phosphoinositide 3-kinase, PI3K inhibitor, inflammation, immune response, immune disorder, cancer, allergy, knockout, therapeutic agent