Abstract
Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug discovery. Recent years have seen an explosion of interest in developing small molecules binding to bromodomains, the readers of acetyl-lysine modifications. A plethora of co-crystal structures has motivated focused fragment-based design and optimization programs within both industry and academia. These efforts have yielded several compounds entering the clinic, and many more are increasingly being used as chemical probes to interrogate bromodomain biology. High selectivity of chemical probes is necessary to ensure biological activity is due to an on-target effect. Here, we review the state-of-the-art of bromodomain-targeting compounds, focusing on the structural basis for their on-target selectivity or lack thereof. We also highlight chemical biology approaches to enhance on-target selectivity.
Highlights
104 Baud MGJ, Lin-Shiao E, Zengerle M, Tallant C, Ciulli A
Inspection of gene tracks for regions differentially occupied by bio-JQ1 provided evidence that bio-JQ1 tends to cooccupy enhancers where there are substantial BRD4 signals, and lower signals for BRD2 and BRD3. These results indicated that the pattern of (+)-JQ1 occupancy of chromatin is most strongly correlated with that of BRD4 in MM1.S cells [116]
Conclusion & future perspective Epigenetic control of gene expression plays a significant role in a variety of diseases, including cancer and inflammation
Summary
The importance of R1173 as a key residue to gain selectivity for CREBBP against BET bromodomains was reinforced by a new series of ligands discovered by an in silico approach, with Kds down to nanomolar range for CREBBP bromodomain [72,73]. A new class of xanthine-based inhibitors (Supplementary Figure 1) discovered using a ‘protein–protein interaction inhibition (2P2I)-oriented’ collection of compounds was able to yield the first described low micromolar selective inhibitor targeting BRD4-BD1 with a greater than tenfold ratio in binding affinity toward any other BET bromodomain. ET achieved up to 540-fold selectivity and no less than 30-fold (average 160-fold) across the entire BET subfamily, and high selectivity was retained within tandem constructs To validate this strategy, x-ray structures of BRD2-BD2L383A in complex with the methylated and ethylated bumped ligands were solved (PDB 4QEV and 4QEW respectively), showing that they adopt the same binding mode as I-BET762 and (+)-JQ1, positioning the respective methyl and ethyl substituents toward the hole introduced by the mutation (Figure 9). The micromolar affinities of these compounds make unlikely that this activity will cause side effects due to inhibition of BET bromodomains
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
