Discovery of the First Potent PI3K/mTOR Dual-Targeting PROTAC Degrader for Efficient Modulation of the PI3K/AKT/mTOR Pathway.
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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 v
APA
Zhu W, Chen J, et al. (2025). Discovery of the First Potent PI3K/mTOR Dual-Targeting PROTAC Degrader for Efficient Modulation of the PI3K/AKT/mTOR Pathway.. Journal of medicinal chemistry, 68(24), 26188-26205. https://doi.org/10.1021/acs.jmedchem.5c02244
MLA
Zhu W, et al.. "Discovery of the First Potent PI3K/mTOR Dual-Targeting PROTAC Degrader for Efficient Modulation of the PI3K/AKT/mTOR Pathway.." Journal of medicinal chemistry, vol. 68, no. 24, 2025, pp. 26188-26205.
PMID
41332195
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 was identified as a potent dual-degrader of both PI3K and mTOR, with DC values of 42.23-227.4 nM (PI3K) and 45.4 nM (mTOR) in MDA-MB-231 cells, also exhibited robust antiproliferative activity in multiple breast cancer cell lines. Mechanistic studies confirmed that achieved degradation through the ubiquitin-proteasome system (UPS). DIA proteomics and RNA-seq confirmed the on-target pathway modulation and revealed potential antileukemia activity. validation showed 's significant tumor growth suppression capability. These findings indicated that , 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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