Issue 2, 2024

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

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.

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

Associated articles

Supplementary files

Article information

Article type
Edge Article
Submitted
01 Sep 2023
Accepted
01 Dec 2023
First published
12 Dec 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 683-691

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

W. T. Jauslin, M. Schild, T. Schaefer, C. Borsari, C. Orbegozo, L. Bissegger, S. Zhanybekova, D. Ritz, A. Schmidt, M. Wymann and D. Gillingham, Chem. Sci., 2024, 15, 683 DOI: 10.1039/D3SC04629J

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