Double Swords in One: Novel Selective PI3<i>K</i>/110β PROTAC Degraders for the Treatment of Multidrug-Resistant Cancer by Activating ERS and Inhibiting P-gp

The p110β isoform of the PI3 kinase (PI3K) family plays a key role in tumorigenesis and PTEN loss-driven multidrug resistance (MDR). Herein, we describe the design, synthesis, and structure-activity relationship studies of a series of small-molecule PI3<i>K</i>/110β PROTACs degraders by combining the selective inhibitor TGX221 of PI3<i>K</i>/110β with VHL ligands. Among them, <b>J-6</b> and <b>J-9</b> exhibited rapid and efficient degradation ability for the target proteins in MDR cells. Meanwhile, the expression and activity of P-glycoprotein were significantly inhibited, leading to a strong synergistic antitumor effect with adriamycin or cisplatin. Further studies confirmed that the two degraders can induce endoplasmic reticulum stress-mediated mitochondrial apoptosis by the AKT/Bcl-2 inhibition-mediated PERK/CHOP-unfolded protein reaction. In vivo studies also verified that the two degraders inhibited the growth of MCF-7/ADM xenograft tumors with high safety. Hence, this study and further optimization of these PI3<i>K</i>/110β PROTAC degraders have broad prospects for the development of new cancer therapies.