CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model.
Ami KetleyMarzena WojciechowskaSonja Ghidelli-DissePaul BamboroughTushar K GhoshMarta Lopez MoratoSaam SedehizadehNaveed Altaf MalikZhenzhi TangPaulina PowalowskaMatthew K TannerRudolf Billeter-ClarkRebecca C TruemanPhilippine C GeiszlerAlessandra AgostiniOthman OthmanMarkus BoescheMarcus BantscheffMartin RüdigerDanuta E MossakowskaDavid Harold DrewryWilliam J ZuercherCharles A ThorntonGerard DrewesIain UingsChristopher J HayesJ David BrookPublished in: Science translational medicine (2021)
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.
Keyphrases
- mouse model
- cell cycle
- small molecule
- protein kinase
- poor prognosis
- clinical trial
- end stage renal disease
- binding protein
- cell cycle arrest
- ejection fraction
- chronic kidney disease
- newly diagnosed
- early onset
- induced apoptosis
- prognostic factors
- cell proliferation
- protein protein
- single cell
- skeletal muscle
- high throughput
- muscular dystrophy
- glycemic control
- randomized controlled trial
- long non coding rna
- stem cells
- genome wide
- adipose tissue
- cell therapy
- case report
- signaling pathway
- dna methylation
- tyrosine kinase
- mesenchymal stem cells
- oxidative stress
- study protocol
- combination therapy
- wild type
- phase ii
- pi k akt