A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα

Class I phosphoinositide 3-kinases (PI3Ks) control cellular growth, but are also essential in insulin signaling and glucose homeostasis. Pan-PI3K inhibitors thus generate substantial adverse effects, a reality that has plagued drug development against this target class. We present here evidence that a high affinity binding module with the capacity to target all class I PI3K isoforms can facilitate selective degradation of the most frequently mutated class I isoform, PI3K alpha, when incorporated into a cereblon-targeted (CRBN) degrader. A systematic proteomics study guided the fine tuning of molecular features to optimize degrader selectivity and potency. Our work resulted in the creation of WJ112-14, a PI3K alpha-specific nanomolar degrader that should serve as an important research tool for studying PI3K biology. Given the toxicities observed in the clinic with unselective PI3K alpha inhibitors, the results here offer a new approach toward selectively targeting this frequently mutated oncogenic driver.Bifunctional degraders built from unselective inhibitors of the phosphoinositide 3-kinase (PI3K) family can support selective degradation of specific isoforms, such as the frequently mutated oncoprotein PI3K alpha.