{"title":"Precise regulation of RAS-Mediated PI3Kα activation: therapeutic potential of BBO-10203 in cancer treatment.","authors":"Ziyi Fan, Erqing Tan, Bin Song","doi":"10.1186/s40164-025-00706-8","DOIUrl":null,"url":null,"abstract":"<p><p>In recent years, the Phosphoinositide-3-Kinase α (PI3Kα) signaling pathway has been increasingly recognized as a critical driver of tumorigenesis, particularly in breast cancer drug resistance and other solid tumors. Although conventional PI3Kα inhibitors (e.g., Alpelisib) have shown efficacy in extending progression-free survival in patients with PI3Kα-mutant breast cancer, their clinical application remains constrained by off-target toxicities, particularly hyperglycemia, which limits dosing and therapeutic feasibility. Building on recent preclinical findings, this study introduces BBO-10203, a first-in-class, orally bioavailable small-molecule inhibitor targeting the RAS-PI3Kα interaction. The compound is rationally designed to selectively and covalently bind to Cysteine 242 (Cys242) within the Rat Sarcoma (RAS)-Binding Domain (RBD) of PI3Kα, thereby effectively disrupting RAS-mediated PI3Kα activation. This unique mechanism confers potent in vivo antitumor activity while preserving insulin-regulated glucose metabolism, thereby mitigating metabolic adverse effects.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"115"},"PeriodicalIF":13.5000,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482239/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Hematology & Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40164-025-00706-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
In recent years, the Phosphoinositide-3-Kinase α (PI3Kα) signaling pathway has been increasingly recognized as a critical driver of tumorigenesis, particularly in breast cancer drug resistance and other solid tumors. Although conventional PI3Kα inhibitors (e.g., Alpelisib) have shown efficacy in extending progression-free survival in patients with PI3Kα-mutant breast cancer, their clinical application remains constrained by off-target toxicities, particularly hyperglycemia, which limits dosing and therapeutic feasibility. Building on recent preclinical findings, this study introduces BBO-10203, a first-in-class, orally bioavailable small-molecule inhibitor targeting the RAS-PI3Kα interaction. The compound is rationally designed to selectively and covalently bind to Cysteine 242 (Cys242) within the Rat Sarcoma (RAS)-Binding Domain (RBD) of PI3Kα, thereby effectively disrupting RAS-mediated PI3Kα activation. This unique mechanism confers potent in vivo antitumor activity while preserving insulin-regulated glucose metabolism, thereby mitigating metabolic adverse effects.
期刊介绍:
Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings.
Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.