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

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

  • Sci Transl Med. 2020 Apr 29;12(541):eaaz2415. doi: 10.1126/scitranslmed.aaz2415.
Ami Ketley 1,  Marzena Wojciechowska 1,  Sonja Ghidelli-Disse 2,  Paul Bamborough 3,  Tushar K Ghosh 1,  Marta Lopez Morato 1,  Saam Sedehizadeh 1,  Naveed Altaf Malik 1,  Zhenzhi Tang 4,  Paulina Powalowska 1 5,  Matthew Tanner 4,  Rudolf Billeter-Clark 1,  Rebecca C Trueman 1,  Philippine C Geiszler 1,  Alessandra Agostini 1,  Othman Othman 1,  Markus Bösche 2,  Marcus Bantscheff 2,  Martin Rüdiger 6,  Danuta E Mossakowska 7 8,  David H Drewry 9,  William J Zuercher 9 10,  Charles A Thornton 4,  Gerard Drewes 2,  Iain Uings 7,  Christopher J Hayes 5,  J David Brook 11
Affiliations

Affiliations

  • 1 School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
  • 2 Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 61997 Heidelberg, Germany.
  • 3 Computational and Modelling Sciences, GlaxoSmithKline, Medicines Research Centre, Hertfordshire SG1 2NY, UK.
  • 4 Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642-0001, USA.
  • 5 School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
  • 6 Screening Profiling and Mechanistic Biology, GlaxoSmithKline, Medicines Research Centre, Hertfordshire SG1 2NY, UK.
  • 7 Discovery Partnerships with Academia, GlaxoSmithKline, Medicines Research Centre, Hertfordshire SG1 2NY, UK.
  • 8 Malopolska Centre of Biotechnology, Jagiellonian University, 30-348 Krakow, Poland.
  • 9 Department of Chemical Biology, GlaxoSmithKline, Research Triangle Park, NC 27709-3398, USA.
  • 10 SGC Center for Chemical Biology, UNC, Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA.
  • 11 School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK. [email protected].
PMID: 32350131 DOI: 10.1126/scitranslmed.aaz2415
Abstract

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.

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