During the Q&A of the Zenith webcast, an audience member asked a question about selective BET inhibitors vs. non-selective pan-BET inhibitors. Don clarified that ZEN-3694 is a pan-BET inhibitor and that apabetalone is a bromodomain-2 (BD-2) selective BET inhibitor. Don also acknowledged that another company has finally come along with a BD-2 selective BET inhibitor. Don kind of fumbled the answer, not knowing if it had entered clinical trials yet and also mentioning (falsely?) that it was a Gilead compound. Perhaps Gilead does have a BD-2 selective BET inhibitor, but that is news to me. The only Gilead BET inhibitor I know of is their pan-BET inhibitor GS-5829, which has been in clinical trials for over 3 years. To my knowledge, the only other company that has a selective BET inhibitor in clinical trials is Abbvie with ABBV-744, which I originally posted about in Feb 2018. 

Abbvie has a Phase 1 oncology clinical trial listed on ClinicalTrials.gov for ABBV-744 that is currently recruiting. First listed December 2017 with anticipated start end of Feb 2018. There is no sign that Abbvie is pursuing ABBV-744 in any indication other than oncology, such as renal or cardiovascular, at this time. Conversely, there is no sign that Resverlogix is pursuing any oncology indications with apabetalone. To my knowledge, the ABBV-744 trial is the first cancer trial using a bromodomain-selective BET inhibitor.

A Study Evaluating the Safety and Pharmacokinetics of ABBV-744 in Subjects With Advanced Prostate Cancer (CRPC) and Relapsed/Refractory Acute Myeloid Leukemia (AML) Cancer

The important thing to keep in mind is that BD selectivity isn't the only determinant to how a BET inhibitor will alter gene expression. Different BET inhibitors may bind slightly differently to the BET protein and alter the structure in a different way, which can have huge implications on how transcription is affected. Apabetalone and ABBV-744 likely have different affinities for BD2, bind to slightly different pockets/amino acid residues in the BD2, and alter the BET conformation in slightly different ways. Small difference translate to big differences in modulation of BET protein control of gene expression. Abbvie claims in their AACR abstract that ABBV-744 has a 300-fold higher affinity for BD2 of BRD4 than BD1 of BRD4. The 2013 paper by Picaud et al. investigated the BD2 selectivity of apabetalone. However, without a side by side comparison of ABBV-744 and apabetalone using the same methodology, I don't think it is fair to compare the two. 

In this paper, they did a focused library screening to identify a series of tetrahydroquinoxalines with high selectivity for BD2 (much more so than apabetalone).

Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain.

https://www.ncbi.nlm.nih.gov/pubmed/29656650