"Similar not same. The sites work TOGETHER. Like picking up a shovel without three fingers, you can do it but it's a lot more difficult. This is probably one reason why RVX208 has been shown to be much less potent than JQ1 on a number of pathways which likely contributes to its good safety profile. 

"The transcriptional effect of (+)-JQ1 is 10x higher than that of RVX-208"

It's more complex than potency, as detailed in my prior post. If it was only about potency, as you imply, then a pan-BET inhibitor could just be dosed at a lower level to achieve the same "less potent" effect of a BD-2 selective inhibitor. As stated before, different inhibitors can have different structures, bind to different regions of the bromodomain acetyl-lysine binding pocket, elicit different conformational shifts in the bromodomain, have different pharmacokinetics, different tissue distribution, have different affinities for BD2 vs. BD1. All of these things influence the unique gene expression changes elicited by different BET inhibitors. Yes, BD1 and BD2 are both required for normal BET function. But selective inhibition of BD1 or BD2 elicit unique transcriptional changes. And even if one compares different BD2 selective inhibitors such as apabetalone, RVX-297 and ABBV-744, they all bind BD2 slightly differently and these differences give rise to a unique gene expression profile change for each inhibitor. With all due respect, trust me I'm a biochemist...LOL.

"Furthermore, based on the abundance of available data on apabetalone, there is simply no way to see the level of impact without targeting the mitochondria. There is no removal of inflammation, no improvement of kidney function, no reduction in atherosclerosis without an improvement in the mitochondria."

Nice hypothesis. Now show me some apabetalone data supporting your hypothesis showing that apabetalone modulates gene expression related to mitochondrial function and  electron transport chain function. The data might exist, but so far you haven't provided  anything to support your hypothesis. You can't rely on data from a pan-BET inhibitor in a cell line to infer apabetalone effects in a whole animal.

BearDownAZ