Discovery and mechanism of action studies of 4,6-diphenylpyrimidine-2-carbohydrazides as utrophin modulators for the treatment of Duchenne muscular dystrophy

Duchenne muscular dystrophy is a fatal disease with no cure, caused by lack of the cytoskeletal protein dystrophin. Upregulation of utrophin, a dystrophin paralogue, offers a potential therapy independent of mutation type. The failure of first-in-class utrophin modulator ezutromid/SMT C1100 in Phase II clinical trials necessitates development of compounds with better efficacy, physicochemical and ADME properties and/or complementary mechanisms. We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter. We further demonstrate through target deconvolution studies, including expression analysis and chemical proteomics, that this compound series operates via a novel mechanism of action, distinct from that of ezutromid. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Duchenne muscular dystrophy is a fatal disease caused by lack of dystrophin, for which upregulation of utrophin offers a potential therapy independent of mutation type. The failure of the first-in-class utrophin modulator in clinical trials calls for the development of compounds with better efficacy. A novel class of utrophin modulators was discovered with a distinct mechanism of action, showing promising potential for treating the disease.