精确调节ras介导的PI3Kα活化:boo -10203在癌症治疗中的治疗潜力。

IF 13.5 1区 医学 Q1 HEMATOLOGY
Ziyi Fan, Erqing Tan, Bin Song
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引用次数: 0

摘要

近年来,磷酸肌醇-3-激酶α (PI3Kα)信号通路越来越被认为是肿瘤发生的关键驱动因素,特别是在乳腺癌耐药和其他实体肿瘤中。尽管传统的PI3Kα抑制剂(如Alpelisib)已显示出延长PI3Kα突变乳腺癌患者无进展生存期的疗效,但其临床应用仍然受到脱靶毒性的限制,特别是高血糖,这限制了剂量和治疗可行性。基于最近的临床前研究结果,本研究引入了BBO-10203,这是一种一流的口服生物可利用小分子抑制剂,靶向RAS-PI3Kα相互作用。该化合物被合理设计为选择性共价结合PI3Kα的大鼠肉瘤(RAS)-结合域(RBD)内的半胱氨酸242 (Cys242),从而有效地破坏RAS介导的PI3Kα活化。这种独特的机制赋予体内有效的抗肿瘤活性,同时保持胰岛素调节的葡萄糖代谢,从而减轻代谢不良反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Precise regulation of RAS-Mediated PI3Kα activation: therapeutic potential of BBO-10203 in cancer treatment.

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.

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来源期刊
CiteScore
12.60
自引率
7.30%
发文量
97
审稿时长
6 weeks
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.
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