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

Abstract

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.

Citation

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. https://doi.org/10.1126/scitranslmed.aaz2415

• 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
• DOI: https://doi.org/10.1126/scitranslmed.aaz2415
• Keywords: General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/4371513
• Publisher URL: https://stm.sciencemag.org/content/12/541/eaaz2415?rss=1