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Message: Bromodomains: a new target class for drug development

A wonderful article published earlier this month in Nature Reviews Drug Discovery.The authors, Andrea G. Cochran, Andrew R. Conery & Robert J. Sims III are from Genentech and Constellation Pharmaceuticals. Nice peer recognition!

"Bromodomains: a new target class for drug development"

https://www.ncbi.nlm.nih.gov/pubmed/31273347

https://www.nature.com/articles/s41573-019-0030-7

I'm not sure if it is open access, but there is a great paragraph on apabetalone acknowledging that it is really the only BET inhibitor with an active trial in an indication other than oncology. It also acknowledges that apabetalone is a bromodomain-2 selective BET inhibitor. I added parentheses around the reference numbers below just to make the formatting easier to read. 

"Non-oncology indications for BETis

BETis can block cytokine production by macrophages and reverse septic shock in mice, and further studies have reported broad anti-inflammatory activity of multiple BETis (30). Beyond inflammatory diseases, BETis reverse cardiac damage in mouse models of heart failure through modulation of cardiomyocyte transcriptional programmes (54). Despite the potential for broad application in inflammatory disease contexts, to date there is only one active trial for BETis in a non-oncology indication (Table 2). Apabetalone (also known as RVX-208 or RVX-000222, developed by Resverlogix) is currently being tested in a phase III trial for patients with high-risk cardiovascular disease with type 2 diabetes mellitus and low high-density lipoprotein (HDL), with the primary end point being a reduction in the number of major cardiac events (55). Preclinical and earlier stage clinical programmes demonstrated beneficial effects of apabetalone on apolipoprotein A1 and HDL levels, glucose metabolism, cholesterol transport, vascular inflammation, coagulation and the complement cascade (56,57,58,59). Although other BETis share some of the pharmacology of this compound, the pleiotropic effects of apabetalone have not been observed with other chemotypes (60,61,62). Conversely, apabetalone has a minimal transcriptional impact on the key oncogenic transcriptional networks targeted by other BETis (63,64). There is some debate over whether the unique pharmacology of apabetalone is the result of preferential binding to BD2 or whether there may be a BD-independent component to its activity (61,63)."

The Table 2 that the passage references is titled "Bromodomain inhibitors in development as single agents in non-oncology indications" and lists 10 trials. 9 of the 10 are past, active or planned Resverlogix trials and the 10th is past completed Phase 1 by GlaxoSmithKline for GSK525762 that seems to be dealing with understanding the pharmacology of this drug in healthy human female subjects.

BearDownAZ

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