Developing selective PI3K degraders to modulate both kinase and non-kinase functions

For the first time, proteolysis-targeting chimeras (PROTAC) technology was utilized to achieve the isoform-selective degradation of class I phosphoinositide 3-kinases (PI3Ks) in this study. Through screening and optimization, the PROTAC molecule ZM-PI05 was identified as a selective degrader of p110α in multiple breast cancer cells. More importantly, the degrader can down-regulate p85 regulatory subunit simultaneously, thereby inhibiting the non-enzymatic functions of PI3K that are independent on p110 catalytic subunits. Therefore, compared with PI3K inhibitor copanlisib, ZM-PI05 displayed the stronger anti-proliferative activity on breast cancer cells. In brief, a selective and efficient PROTAC molecule was developed to induce the degradation of p110α and concurrent reduction of p85 proteins, providing a tool compound for the biological study of PI3K-α by blocking its enzymatic and non-enzymatic functions.