"It's not a stretch at all. BD1 and BD2 serve complementary functions. By inhibiting one, you are still able to inhibit the combined function."
Pomp, to me it sounds like you are implying that inhibitting BD1 and/or BD2 all elicit the same effect on the BET protein and biological outcome. This is not true. Even the paper you cite argues against your proposal:
"Collectively, our results suggest that selective inhibition of the first BrD (such as by Olinone or MS611) facilitates the progression of primary oligodendrocyte progenitors toward a differentiated phenotype, inhibition of the second BrD (such as by MS765/RVX-208) has no effect, and inhibition of both BrDs of BET proteins (such as MS417) negatively affects the differentiation process"
Not all BD-2 selective BET inhibitors are created equal. Not all BD-1 selective BET inhibitors are created equal. Not all pan-BET inhibitors are created equal. 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, and cause different gene expression changes.
Of course, some of this is concentration dependent. At a high enough concentration, even a BD2 selective BET inhibitor will bind and robustly inhibit BD1, and vice versa. But at optimal concentrations, there is still BD selectivity for BD-selective inhibitors. Pan-BET inhibitors have been extensively studies for oncology and come with significant toxicity issues. If BD2 inhibition compromises BD1 function, or vice versa, one would predict that BD-selective inhibitors would act the same as pan-BET inhibitors. This has been shown in numerous studies to not be the case. Why would Resverlogix and Zenith tout their extensive compound libraries with different bromodomain selectivities if this didn't matter?
See this post on bromodomain vs BET protein selectivity. See this post on RVX-297. See this post on ABBV-744.
BearDownAZ
