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

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.

Automated summary

The Ser/Thr protein kinase Wee1 plays a regulatory role in DNA damage by phosphorylating CDK1. The selective inhibitor AZD1775 has off target effects on other protein kinases. This study describes the synthesis and evaluation of Wee1-degrading PROTACs with different linkers.