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

Aublette, Marine C and Harrison, Tom A and Thorpe, Elizabeth J and Gadd, Morgan S (2022) Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases. Bioorganic & medicinal chemistry letters, 64. ISSN 1464-3405

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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.

Item Type:
Journal Article
Journal or Publication Title:
Bioorganic & medicinal chemistry letters
Subjects:
ID Code:
178106
Deposited By:
Deposited On:
25 Oct 2022 10:25
Refereed?:
Yes
Published?:
Published
Last Modified:
22 Nov 2022 11:15