Discovery and optimization of novel, selective HDAC11 inhibitors for the treatment of obesity and related diseases.

Project Summary/Abstract Significant advancements in pharmacotherapy for obesity have recently been realized, as exemplified by GLP- 1 receptor agonists, which reduce appetite and function as incretin mimetics by promoting pancreatic insulin release. It may be possible to further improve metabolic health using agents that target distinct molecular mechanisms that impinge on adipose tissue (AT) to promote energy expenditure and ameliorate fat dysfunction, hallmarks of which are insulin resistance, inflammation and fibrosis. In this regard, there is interest in developing drugs that directly augment brown AT (BAT) function and/or stimulate white AT (WAT) ‘beiging’ as a means of treating metabolic disease. A key feature of BAT/WAT activation is elevated expression of uncoupling protein-1 (UCP1), which uncouples electron transport from ATP synthesis, resulting in non-shivering thermogenesis and energy expenditure. We found that global or adipocyte-specific deletion of the zinc-dependent enzyme, histone deacetylase 11 (HDAC11), in mice prevents weight gain and improves overall metabolic health (e.g., enhanced glucose tolerance and reduced liver steatosis) in the face of chronic high-fat feeding. The salutary effects of HDAC11 knockout (KO) are linked to increased abundance and function of BAT and beiging of WAT, as evidenced by dramatic augmentation of UCP1 expression in KO mice. Despite its name, HDAC11 functions as a lysine demyristoylase as opposed to a deacetylase, with a catalytic efficiency >10,000-fold higher for myristoyl-lysine versus acetyl-lysine. FT895, which is a potent and selective inhibitor of HDAC11 demyristoylase activity, also stimulates UCP1 expression in mouse AT in vivo, and in human AT ex vivo, validating the potential of HDAC11 inhibitors to alter AT phenotype to improve metabolic health. However, despite its utility as a ‘tool compound’, FT895 lacks the pharmaceutical properties required for development of a drug to treat human disease, in part due to the fact that it is a hydroxamic acid-containing HDAC inhibitor. To circumvent this issue, with prior NIH funding (DK119594), we completed a high throughput screening campaign to discover non-hydroxamic acid HDAC11 inhibitors. Using commercially purchased compounds, our hit expansion efforts revealed compelling structure-activity-relationships that validate these inhibitors. We have six series of compounds to potentially pursue in the hit-to-lead/lead discovery phase of the project. Myracle Therapeutics was founded in 2023 with the goal of developing HDAC11 inhibitors to treat obesity and obesity-related diseases. Myracle is in-licensing the aforementioned portfolio of non-hydroxamic acid HDAC11 inhibitor hit compounds. In work outlined in two specific aims, up to two series of Myracle HDAC11 inhibitors will be advanced into a hit-to-lead campaign to discover lead compounds and set the stage for subsequent lead optimization and Investigation New Drug filing.