A ‘click’ chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras

Jasmine M. Cross; Megan E. Coulson; Joshua P. Smalley; Wiktoria A. Pytel; Ozair Ismail; Justin S. Trory; Shaun M. Cowley; James T. Hodgkinson

doi:10.1039/D2MD00199C

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A ‘click’ chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras†

Jasmine M. Cross,^a Megan E. Coulson,

^ab Joshua P. Smalley,^a Wiktoria A. Pytel,^ab Ozair Ismail,^a Justin S. Trory,

^a Shaun M. Cowley*^b and James T. Hodgkinson

*^a

Author affiliations

* Corresponding authors

^a Leicester Institute of Structural and Chemical Biology, School of Chemistry, University of Leicester, Leicester, UK
E-mail: JTHodgkinson@le.ac.uk

^b Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
E-mail: smc57@leicester.ac.uk

Abstract

Click chemistry was utilised to prepare a library of PROTACs based on entinostat a class I histone deacetylase (HDAC) inhibitor in clinical trials. A novel PROTAC JMC-137 was identified as a HDAC1/2 and HDAC3 degrader in HCT116 cells. However, potency was compromised compared to previously identified class I HDAC PROTACs highlighting the importance in the choice of HDAC ligand, functional group for linker attachment and positioning in PROTAC design.

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Article information

DOI: https://doi.org/10.1039/D2MD00199C
Article type: Research Article
Submitted: 28 Jun 2022
Accepted: 05 Oct 2022
First published: 01 Nov 2022
This article is Open Access

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RSC Med. Chem., 2022,13, 1634-1639

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A ‘click’ chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras

J. M. Cross, M. E. Coulson, J. P. Smalley, W. A. Pytel, O. Ismail, J. S. Trory, S. M. Cowley and J. T. Hodgkinson, RSC Med. Chem., 2022, 13, 1634 DOI: 10.1039/D2MD00199C

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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RSC Medicinal Chemistry

A ‘click’ chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras†

Abstract

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A ‘click’ chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras

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