Discovery and Optimization of Potent PROTAC Degraders of Phosphoinositide 3-Kinase with Significant <i>in Vivo</i> Anticancer Efficacy

The aberrant activation of the phosphoinositide 3-kinase (PI3K) pathway is closely linked to the progression of various cancers, highlighting its significance as a target for cancer therapy. In contrast to conventional PI3K inhibitors, the selective degradation of PI3K protein via PROTAC technology presents a complementary therapeutic strategy. In this work, a 4-methylquinazoline based scaffold designed to bind to PI3K was conjugated with a CRBN ligand via an appropriate linker, leading to the discovery of a series of novel PI3K PROTAC degraders. Among them, degrader <b>12</b> was demonstrated to show selective degradation activity against PI3Kα, with a DC₅₀ value of 0.08 μM. In HGC-27 and T47D cancer cells, degrader <b>12</b> effectively degraded PI3Kα in a time- and concentration-dependent manner and potently inhibited the phosphorylation of AKT at the Ser473 site. Furthermore, with acceptable <i>in vitro</i> and <i>in vivo</i> pharmacokinetic properties, degrader <b>12</b> showed significant <i>in vivo</i> anticancer efficacy in HGC-27 and DOHH2 xenograft models.