Development of small-molecule inhibitors that target PI3Kβ.

Yanzhen Yu, Dongyan Gu, Lvtao Cai, Haodong Yang, Rong Sheng

Journal: Drug discovery today 2024;29(1):103854

PMID: 38070704

Full Text on Elsevier Science View on PubMed

Abstract

Phosphatidylinositol-3 kinase (PI3K) β, a subtype of class I PI3Ks, has an essential role in PTEN-deficient tumors and links to thrombosis, male fertility, and Fragile X syndrome. PI3Kβ-specific targeting therapy could be an efficacious treatment for diseases highly dependent on PI3Kβ, while mitigating the severe toxicity of pan-PI3K inhibitors. Achieving selectivity can be accomplished through three primary strategies, namely, binding to the induced lipophilic pocket, targeting the unique amino acid residue of PI3Kβ, or using atropisomerism to lock conformation. In this review, we focus on advances in the development of these β-isoform-selective PI3K inhibitors, providing potential guidance for the further development of novel clinical candidates.

Address: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Jinhua Institute of Zhejiang University, Jinhua, Zhejiang 321000, PR China.; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Jinhua Institute of Zhejiang University, Jinhua, Zhejiang 321000, PR China. Electronic address: [email protected].

DOI: 10.1016/j.drudis.2023.103854

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https://linkinghub.elsevier.com/retrieve/pii/S1359...

MeSH Terms: Male, Humans, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Molecular Conformation, Protein Kinase Inhibitors