CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model
Ami Ketley(University of Nottingham), Marzena Wojciechowska(University of Nottingham), Sonja Ghidelli‐Disse(GlaxoSmithKline (Germany)), Paul Bamborough(GlaxoSmithKline (United Kingdom)), Tushar K. Ghosh(University of Nottingham), Marta López-Morató(University of Nottingham), Saam Sedehizadeh(University of Nottingham), Naveed Altaf Malik(University of Nottingham), Zhenzhi Tang(University of Rochester Medical Center), Paulina Klaudyna Powalowska(University of Nottingham), Matthew Tanner(University of Rochester Medical Center), R. Billeter(University of Nottingham), Rebecca C. Trueman(University of Nottingham), Philippine C. Geiszler(University of Nottingham), Alessandra Agostini(University of Nottingham), Othman Ahmad Othman(University of Nottingham), Markus Bösche(GlaxoSmithKline (Germany)), Marcus Bantscheff(GlaxoSmithKline (Germany)), Martin Rüdiger(GlaxoSmithKline (United Kingdom)), Danuta E. Mossakowska(Jagiellonian University), David H. Drewry(Research Triangle Park Foundation), William J. Zuercher(University of North Carolina at Chapel Hill), Charles A. Thornton(University of Rochester Medical Center), Gerard Drewes(GlaxoSmithKline (Germany)), Iain Uings(GlaxoSmithKline (United Kingdom)), Christopher J. Hayes(University of Nottingham), J. David Brook(University of Nottingham)
Cited by 22Open Access
Abstract
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.
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