Developing CDK12 inhibitors to treat Myotonic Dystrophy

Our aim is to develop a treatment for Myotonic Dystrophy type 1 (DM1), which is a severe, progressive, debilitating condition which affects a range of systems including skeletal muscle heart and brain. There is currently no treatment available for this condition. DM1 is caused by an unusual mutation in a gene called DMPK. It is called an expansion mutation because a short sequence of DNA is greatly expanded with DM1. The faulty DNA is made into RNA which gets trapped in the nuclei of patient's cells where it forms distinct spots or foci, detectable down a microscope. We developed an assay to identify small molecules that get rid of the spots in patient's cells as they would provide the starting point to develop a treatment for DM1. Drug discovery programmes typically identify what is known as a druggable target, that is a protein that can be targeted with a small molecule. We have shown that the set of small molecule inhibitors that remove nuclear foci have as their common target a protein called cyclin-dependent kinase 12 (CDK12). We have also shown that CDK12 co-locates with repeat expansion foci in DM1 cells and its levels are elevated in DM1 cell lines and in DM1 patient muscle biopsies. Quite a bit is known about CDK12 as it is important for modifying other proteins in particular one called RNA polymerase II. It plays a role in the stress response, and it is involved in the transcription (making RNA from) of long genes. It may also play a role in other processes within the cell. Despite the many possible roles for CDK12 we think it makes a good target for DM1 therapy. For example a genetically modified mutant mouse has been produced which lacks one copy of the Cdk12 gene and these mice called knockout mice, lacking a copy of Cdk12 are viable and appear perfectly normal. This gives us confidence that we should be able to reduce to normal the increased levels of Cdk12 in DM1 patients. We expect such a reduction to prevent the patient's cells making the faulty RNA and eliminate the spots we see down the microscope. Our initial results suggest this may be possible. We have undertaken a drug development programme to produce novel and selective CDK12 inhibitors. We have shown that these compounds affect CDK12 and reduce the levels of repeat expansion RNA, removing nuclear foci in patient-derived cell lines. Our lead compound showed encouraging activity in an in vivo study using a mouse model of DM1. Thus, our lead series of molecules are excellent candidates for further development for treatment of DM1 and this project is focussed on completing a drug development programme, called a Lead Optimisation investigation to progress our molecules towards pre-clinical studies.