Thanks for posting Cabel. This "Next Generation Epigenetic Inhibitors" article is a great perspective/preview by Panagis Filippakopoulos and Stefan Knapp that focuses on new and improved BET inhibitors with better BD1 vs. BD2 selectivity. It summarizes the troubles that pan-BET inhibitors have encountered and highlights the potential for BD-selective inhibitors. It does mention RVX-208/apabetalone:

"Early indications that domain selectivity might be achievable came from relatively weak BET inhibitors such as RVX-208 that exhibits ~8- to 20-fold selectivity for BD2 over BD1 (9). This inhibitor interacted with a histidine located at the rim of the acetyl-lysine–binding site, which is conserved in all BD2s, but not in BD1s (which harbor an aspartate at this position). This residue variation has been exploited in the development of the BD2-selective inhibitor ABBV-744 (10)."

It also briefly covers the much more BD-2 selective ABBV-744. But it is mainly a preview of the main article in Science by Omer Gilan and others "Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation" that reports on new compounds from GSK: "GSK046 (iBET-BD2) , a potent BD2-selective inhibitor with >1000-fold selectivity over BD1. They also report on the development of GSK620, an orally bioavailable BD2-selective inhibitor, and GSK778 (iBET-BD1), a BD1-selective inhibitor."

I haven't read the Gilan article yet, but here is the main takeaway from the abstract "We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease."

The intro of this issue of Science also has a bit "Bromodomain inhibitors revisited by Paula A. Kiberstis

Bromodomain and extraterminal domain (BET) proteins contribute to the pathogenesis of cancer and immune diseases through their effects on transcriptional regulation. BET proteins contain two nearly identical bromodomains, BD1 and BD2, structural modules that have attracted great interest as targets for drug development. First-generation drugs that inhibited both BD1 and BD2 showed promising therapeutic activity in preclinical models but proved to be less efficacious in clinical trials. Gilan et al. took a different approach and designed drugs that selectively inhibited BD1 or BD2 (see the Perspective by Filippakopoulos and Knapp). They found that BD1 and BD2 inhibitors altered gene expression in different ways and that BD2 inhibitors had greater therapeutic activity than BD1 inhibitors in preclinical models of inflammation and autoimmune disease."

BDAZ