Wentao Zhu, Jian Chen, Wenqian Zhang, Yinmiao Wang, Fang Xu, Jiyan Pang
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.