Developing drugs to target CDK12 as a treatment for myotonic dystrophy (360G-Wellcome-107562_Z_15_Z)

Myotonic Dystrophy type 1 is the most common adult muscular dystrophy. It is an orphan disease for which there is no treatment. It is caused by a repeat expansion mutation in the 3' untranslated region of the DMPK gene. When expressed the DMPK expansion transcripts remain in the nucleus where they form foci. We have demonstrated a significant role for CDK12 in foci formation and treatment with a CDK12 inhibitor leads to the dissolution of foci and degradation of the mutant transcripts. This work points to CDK12 as a novel target for small molecule development as a treatment for DM1. In this proposal we outline our approach to identify a lead compound with CDK12 activity and selectivity profiles suitable for further optimisation. Our approach outlines a medicinal chemistry plan based on the CDK12 structure with ADME and selectivity assays to establish cytotoxicity and pharmacodynamics. We will test compounds in DM1 cell lines to examine their effect on key molecular features of the disorder and we will examine the effect of compounds in the HSALR mice which represent the best available DM model. Thus, we intend to identify a lead series for myotonic dystrophy treatment and generate significant IP for CDK12 inhibitors.