Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases

Aublette, MC; Harrison, TA; Thorpe, EJ; Gadd, MS

Abstract

The Ser/Thr protein kinase Wee1 plays a regulatory role at the G(2)/M checkpoint by phosphorylating CDK1 when DNA is damaged to allow time for DNA to repair, disruption of which is a key approach to sensitise cancer cells to DNA-damaging therapies. The main selective inhibitor for Wee1 undergoing development in clinical trials, AZD1775, however, has been shown to have off target effects towards other protein kinases with similar potency. Here we describe the synthesis and assessment of a series of Wee1-degrading PROTACs using AZD1775 linked to either the VHL ligand VH032 or to the CRBN ligand pomalidomide using different types and lengths of linkers. The conversion of AZD1775 into a PROTAC induces selective Wee1 degradation for compounds of both series depending on the nature of the linker.

Keywords: Wee1; CDK1; Checkpoint inhibition; PROTAC; Targeted degradation; VHL; Cereblon

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PROTAC

PROTAC (Proteolysis Targeting Chimeras) is a revolutionary drug design strategy for specifically degrading proteins. It consists of two functional domains: a binding domain that recognizes target proteins and a ubiquitin-linked domain that induces protein degradation. PROTAC works by binding the target protein to an E3 ubiquitin ligase, thereby marking a specific site on the target protein, causing it to be ubiquitinated and ultimately degraded by the proteasome. This protein-specific degradation method has clear advantages over traditional target inhibitors because it not only reduces the amount of the target protein, but also reduces the functions associated with it. PROTAC technology has been used to treat a variety of diseases, especially cancer and neurodegenerative diseases. In cancer treatment, PROTAC can target and degrade cancer-related proteins, such as kinases, receptors, and transcription factors, thereby inhibiting tumor growth and spread. In addition, PROTAC can also be used to study biological processes and discover new drug targets, bringing new possibilities to the field of drug research and development.