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Discovery of the First Potent PI3K/mTOR Dual-Targeting PROTAC Degrader for Efficient Modulation of the PI3K/AKT/mTOR
Wentao Zhu1, Jian Chen1, Wenqian Zhang1
1School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China.
Abstract:
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical regulator of cell growth and metabolism, and its dysregulation is implicated in various cancers. In this study, a series of dual-target degraders simultaneously targeting PI3K and mTOR was designed and synthesized. Compound GP262 was identified as a potent dual-degrader of both PI3K and mTOR, with DC50 values of 42.23-227.4 nM (PI3K) and 45.4 nM (mTOR) in MDA-MB-231 cells, GP262 also exhibited robust antiproliferative activity in multiple breast cancer cell lines. Mechanistic studies confirmed that GP262 achieved degradation through the ubiquitin-proteasome system (UPS). DIA proteomics and RNA-seq confirmed the on-target pathway modulation and revealed potential antileukemia activity. In vivo validation showed GP262's significant tumor growth suppression capability. These findings indicated that GP262, as the first dual-targeted degrader of PI3K and mTOR, had great potential in the treatment of breast cancer and leukemia.
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