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CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model

Ketley, Ami; Wojciechowska, Marzena; Ghidelli-Disse, Sonja; Bamborough, Paul; Ghosh, Tushar K.; Morato, Marta Lopez; Sedehizadeh, Saam; Malik, Naveed Altaf; Tang, Zhenzhi; Powalowska, Paulina; Tanner, Matthew; Billeter-Clark, Rudolf; Trueman, Rebecca C.; Geiszler, Philippine C.; Agostini, Alessandra; Othman, Othman; B�sche, Markus; Bantscheff, Marcus; R�diger, Martin; Mossakowska, Danuta E.; Drewry, David H.; Zuercher, William J.; Thornton, Charles A.; Drewes, Gerard; Uings, Iain; Hayes, Christopher J.; Brook, J. David

CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model Thumbnail


Research Fellow

Marzena Wojciechowska

Sonja Ghidelli-Disse

Paul Bamborough

Tushar K. Ghosh

Marta Lopez Morato

Saam Sedehizadeh

Naveed Altaf Malik

Zhenzhi Tang

Paulina Powalowska

Matthew Tanner

Philippine C. Geiszler

Alessandra Agostini

Othman Othman

Markus B�sche

Marcus Bantscheff

Martin R�diger

Danuta E. Mossakowska

David H. Drewry

William J. Zuercher

Charles A. Thornton

Gerard Drewes

Iain Uings

Professor of Organic Chemistry

Professor of Human Genetics


Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Myotonic dystrophy type 1 (DM1) is an RNA-based disease with no current treatment. It is caused by a transcribed CTG repeat expansion within the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Mutant repeat expansion transcripts remain in the nuclei of patients' cells, forming distinct microscopically detectable foci that contribute substantially to the pathophysiology of the condition. Here, we report small-molecule inhibitors that remove nuclear foci and have beneficial effects in the HSALR mouse model, reducing transgene expression, leading to improvements in myotonia, splicing, and centralized nuclei. Using chemoproteomics in combination with cell-based assays, we identify cyclin-dependent kinase 12 (CDK12) as a druggable target for this condition. CDK12 is a protein elevated in DM1 cell lines and patient muscle biopsies, and our results showed that its inhibition led to reduced expression of repeat expansion RNA. Some of the inhibitors identified in this study are currently the subject of clinical trials for other indications and provide valuable starting points for a drug development program in DM1.


Ketley, A., Wojciechowska, M., Ghidelli-Disse, S., Bamborough, P., Ghosh, T. K., Morato, M. L., …Brook, J. D. (2020). CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model. Science Translational Medicine, 12(541), Article eaaz2415.

Journal Article Type Article
Acceptance Date Feb 25, 2020
Online Publication Date Apr 29, 2020
Publication Date Apr 29, 2020
Deposit Date May 7, 2020
Publicly Available Date Oct 30, 2020
Journal Science Translational Medicine
Print ISSN 1946-6234
Electronic ISSN 1946-6242
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 12
Issue 541
Article Number eaaz2415
Keywords General Medicine
Public URL
Publisher URL


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