克拉斯
癌症研究
清脆的
癌基因
突变
生物
化学
癌症
结直肠癌
细胞周期
遗传学
基因
作者
Kyle Begovich,Angela Schoolmeesters,Navin Rajapakse,Elena Martínez‐Terroba,Maneesh Kumar,Arvind Shakya,Chon Lai,Steven Greene,Brandon Whitefield,Akinori Okano,Venkat Mali,Shenlin Huang,Aparajita H. Chourasia,Leah Fung
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2024-02-21
卷期号:: OF1-OF14
被引量:1
标识
DOI:10.1158/1535-7163.mct-23-0513
摘要
Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. Given its upstream role in the activation of KRAS, son of sevenless homolog 1 (SOS1), has emerged as an attractive therapeutic target. Agents that target SOS1 for degradation could represent a potential pan-KRAS modality that may be capable of circumventing certain acquired resistance mechanisms. Here, we report the development of two SOS1 cereblon-based bifunctional degraders, BTX-6654 and BTX-7312, cereblon-based bifunctional SOS1 degraders. Both compounds exhibited potent target-dependent and -specific SOS1 degradation. BTX-6654 and BTX-7312 reduced downstream signaling markers, pERK and pS6, and displayed antiproliferative activity in cells harboring various KRAS mutations. In two KRAS G12C xenograft models, BTX-6654 degraded SOS1 in a dose-dependent manner correlating with tumor growth inhibition, additionally exhibiting synergy with KRAS and MEK inhibitors. Altogether, BTX-6654 provided preclinical proof of concept for single-agent and combination use of bifunctional SOS1 degraders in KRAS-driven cancers.
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