Progress in the Development of non‐BET Bromodomain Chemical Probes

Abstract

The bromodomain and extra terminal (BET) family of bromodomains have been the focus of extensive research, leading to the development of many potent, selective chemical probes and recent clinical assets. The profound biology associated with BET bromodomain inhibition has provided a convincing rationale for targeting bromodomains for the treatment of disease. However, the BET family represents just eight of the at least 56 human bromodomains identified to date. Until recently, there has been significantly less interest in non-BET bromodomains, leaving a vast area of research and the majority of this new target class yet to be thoroughly investigated. It has been widely reported that several non-BET bromodomain containing proteins are associated with various diseases including cancer and HIV. Therefore, the development of chemical probes for non-BET bromodomains will facilitate elucidation of their precise biological roles and potentially lead to the development of new medicines. This review summarises the progress made towards the development of non-BET bromodomain chemical probes to date. In addition, we highlight the potential for future work in this new and exciting area.

Clinical progress and pharmacology of small molecule bromodomain inhibitors

“…With comparatively little known about bromodomains outside of the BET family, high quality chemical probes are an important tool for unravelling the biological role of these Clinical progress and pharmacology of small molecule bromodomain inhibitors Theodoulou et al 59 proteins [26 ,27]. There have been many important contributions from both academic and industrial laboratories in the development and biological testing of non-BET bromodomain chemical probes which have been covered in multiple reviews [8][9][10][11][12][13][14]28]. Because of the profound and wide-ranging biology associated with BET family bromodomain inhibition, BET selectivity is an essential characteristic during generation of a chemical probe and in this review we focus on the recent developments of those non-BET bromodomain chemical probes with a reported structure, selectivity over the BET family and demonstrated pharmacology ( Figure 2).…”

Advancements in the Development of non‐BET Bromodomain Chemical Probes

“…In 2016, three patent applications from Genentech and Constellation Pharmaceuticals were released disclosing a number of highly potent PCAF/GCN5 dual inhibitors spanning three different chemotypes. Exemplified by compounds 6 , 7 , and single unknown diastereomer 8 (Figure a), (the most active analogues from each series) each chemotype demonstrated significant improvements in PCAF/GCN5 potency relative to the previously reported PCAF inhibitors . Due to the nature of patent applications, little is known about the selectivity, permeability, solubility and cellular activity of any of the disclosed compounds, thus, it is impossible to comment on their ability to function as PCAF/GCN5 chemical probes.…”

“…With BCP dysregulation implicated in several disease states, there has been a surge of interest in non‐BET bromodomain chemical probes to aid target validation of these epigenetic reader modules. This area was reviewed previously in 2015 by three of the authors of this manuscript . Since this review, however, the field has progressed rapidly with the first non‐BET bromodomain inhibitor entering clinical trials as well as a number of new chemical probes being developed and disclosed (Figure ) .…”

“…This area was reviewed previously in 2015 by three of the authors of this manuscript. [13] Since this review,h owever,t he field has progressedr apidly with the first non-BETb romodomaini nhibitor entering clinical trialsa sw ell as an umber of new chemical probesb eing developed and disclosed ( Figure 2). [14,15] The quality of non-BETb romodomainc hemical probes, and the variety of chemotypes included, has also advanced dramatically, reflecting the awareness and uptake of the guidelines mentioned previously.T he generation of high quality chemical probes, and the structurali nformation typically obtained during their development, has also facilitated the evolution of more sophisticated bifunctionalc hemical biology tools.…”

Small Molecules and Their Role in Effective Preclinical Target Validation

“…In addition to being highquality, well-characterized chemical probes, they were both also accompanied by a negative control in the form of their inactive enantiomer, allowing for phenotypic screening studies [6]. Instead of keeping this information to themselves, the structures and properties of both molecules were made available for the scientific community.…”