A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα
Werner Theodor Jauslin, Matthias Schild, Thorsten Schaefer, Chiara Borsari, Clara Orbegozo, Lukas Bissegger, Saule Zhanybekova, Danilo Ritz, Alexander Schmidt, Matthias P. Wymann, Dennis Gillingham
Abstract
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, PI3Kα, 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 PI3Kα-specific nanomolar degrader that should serve as an important research tool for studying PI3K biology. Given the toxicities observed in the clinic with unselective PI3Kα inhibitors, the results here offer a new approach toward selectively targeting this frequently mutated oncogenic driver.