The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is a central regulator of cancer progression, with frequent activation of the PI3Kα catalytic subunit (p110α) in breast cancer. Here, an integrated in silico to experimental workflow was applied to systematically identify dietary phytochemicals capable of inhibiting PI3Kα and suppressing cancer cell proliferation. A curated PhytoHub library comprising 1966 food-derived compounds was screened by molecular docking against the PI3Kα catalytic domain, followed by isoform-specific enzymatic validation and cellular evaluation. Several flavonoids demonstrated strong PI3Kα inhibition at 30 μM, with jaceosidin and luteolin exhibiting the highest potency (IC₅₀ ≤ 0.1 and 0.76 μM, respectively), whereas anthocyanidins delphinidin and petunidin showed weaker activity. In MCF-7 breast cancer cells, myricetin, delphinidin, apigenin, and kaempferol produced the strongest antiproliferative effects (~55-65% inhibition; p < 0.05). These findings identify flavone-type scaffolds as potent PI3Kα inhibitors and highlight dietary flavonoids as promising functional food bioactives targeting oncogenic signaling.

2026-09-02·EXPERT OPINION ON THERAPEUTIC PATENTS

A patent review of mutant-selective PI3Kα inhibitors for the treatment of different cancers (2021–2025)

Review

作者: Wen, Jiayang ; Qi, Haixiang ; Xu, Heng

INTRODUCTION:

Oncogenic PIK3CA mutations drive numerous solid tumors, rendering PI3Kα a key therapeutic target. However, conventional ATP-competitive inhibitors are severely limited by dose-limiting metabolic toxicities caused by wild-type PI3Kα inhibition. To circumvent these limitations, the drug discovery landscape is rapidly shifting toward mutant-selective allosteric inhibitors designed to spare physiological signaling and expand the therapeutic window.

AREAS COVERED:

Utilizing the Cortellis Drug Discovery Intelligence (CDDI) database, this review evaluates patents of PI3Kα mutant-selective inhibitors disclosed between 2021 and 2025. The analysis focuses on structural features, pharmacological profiles, and medicinal chemistry strategies employed to achieve high selectivity for oncogenic mutants over the wild-type enzyme. Specifically, we examine the binding modes across two distinct allosteric domains: an H1047R-specific pocket and a pan-mutant cryptic site.

EXPERT OPINION:

Mutant-selective allosteric inhibitors achieve selectivity by targeting mutant residues or exploiting unique protein conformational dynamics. The rapidly diversifying patent landscape provides broader opportunities for the discovery of superior inhibitors. Furthermore, development of allosteric inhibitor-based PROTACs is discussed as a promising frontier for enhancing therapeutic precision. Ultimately, deeper understanding of evolving resistance mechanisms provides the design principles required to develop next-generation PI3Kα therapeutics capable of overcoming clinical resistance.

2026-08-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Benzothiophene-based, orally active PIK3CA H1047R mutant-selective inhibitors for the treatment of HR+/HER2- breast cancer

Article

作者: Xu, Hang ; Jin, Lei ; Yang, Fanglong ; Wang, Siqin ; Jia, Xiangyu ; Fan, Xing ; Xia, Yuanfeng ; Zhao, Sheng ; Lu, Biao

PI3Kα plays a key role in a variety of cellular processes, and its gene mutations are closely related to the occurrence and development of many types of cancer. Although two orthosteric PI3Kα inhibitors including Alpelisib and Inavolisib have been launched onto market, they often cause toxic and side effects due to insufficient selectivity for PIK3CA mutant protein. The development of allosteric PI3Kα inhibitors provides new ideas for overcoming these problems. Our research focuses on optimizing a novel series of allosteric PI3Kα inhibitors derived from STX-478. By integrating scaffold hopping and comprehensive structural modification strategies, we obtained the lead compound allosteric PI3Kα inhibitor 11f with a benzothiophene scaffold. The inhibitor demonstrates high selectivity for PIK3CA mutant protein, low hERG inhibition, minimal CYP inhibition, excellent in vivo efficacy, good safety and no impact on insulin balance. Collectively, these findings confirm that compound 11f is a highly promising drug candidate for the targeted therapy of PIK3CA H1047R mutant HR+/HER2-breast cancer.

100 项与 PI3Kα inhibitors(Black Diamond Therapeutics) 相关的药物交易

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