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

Research output: Contribution to Journal/Magazine › Journal article › peer-review

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Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases. / Aublette, Marine C; Harrison, Tom A; Thorpe, Elizabeth J et al.

In: Bioorganic & medicinal chemistry letters, Vol. 64, 128636, 15.05.2022.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Aublette, MC, Harrison, TA, Thorpe, EJ & Gadd, MS 2022, 'Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases', Bioorganic & medicinal chemistry letters, vol. 64, 128636. https://doi.org/10.1016/j.bmcl.2022.128636

APA

Aublette, M. C., Harrison, T. A., Thorpe, E. J., & Gadd, M. S. (2022). Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases. Bioorganic & medicinal chemistry letters, 64, [128636]. https://doi.org/10.1016/j.bmcl.2022.128636

Vancouver

Aublette MC, Harrison TA, Thorpe EJ, Gadd MS. Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases. Bioorganic & medicinal chemistry letters. 2022 May 15;64:128636. Epub 2022 Feb 26. doi: 10.1016/j.bmcl.2022.128636

Author

Aublette, Marine C ; Harrison, Tom A ; Thorpe, Elizabeth J et al. / Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases. In: Bioorganic & medicinal chemistry letters. 2022 ; Vol. 64.

Bibtex

@article{0f180c9d419448ec93486f360a69557f,
title = "Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases",
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 = "CDK1, VHL, targeted degradation, Wee1, cereblon, PROTAC, checkpoint inhibition",
author = "Aublette, {Marine C} and Harrison, {Tom A} and Thorpe, {Elizabeth J} and Gadd, {Morgan S}",
year = "2022",
month = may,
day = "15",
doi = "10.1016/j.bmcl.2022.128636",
language = "English",
volume = "64",
journal = "Bioorganic & medicinal chemistry letters",
issn = "1464-3405",

}

RIS

TY - JOUR

T1 - Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases

AU - Aublette, Marine C

AU - Harrison, Tom A

AU - Thorpe, Elizabeth J

AU - Gadd, Morgan S

PY - 2022/5/15

Y1 - 2022/5/15

N2 - 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.

AB - 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.

KW - CDK1

KW - VHL

KW - targeted degradation

KW - Wee1

KW - cereblon

KW - PROTAC

KW - checkpoint inhibition

U2 - 10.1016/j.bmcl.2022.128636

DO - 10.1016/j.bmcl.2022.128636

M3 - Journal article

C2 - 35231578

VL - 64

JO - Bioorganic & medicinal chemistry letters

JF - Bioorganic & medicinal chemistry letters

SN - 1464-3405

M1 - 128636

ER -