Epigenetics Discovery Performance Unit, GlaxoSmithKline R&D, Stevenage, Hertfordshire, SG1 2NY, UK.
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Thomas Graham Building, Glasgow, G1 1XL, UK.
ChemMedChem. 2019 Feb 19;14(4):362-385. doi: 10.1002/cmdc.201800738. Epub 2019 Feb 4.
The bromodomain and extra terminal (BET) family of bromodomain-containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high-quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non-BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non-BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non-BET bromodomains as tractable therapeutic targets.
过去十年中，溴结构域和末端（BET）家族的溴结构域蛋白（BCP）一直是广泛研究的主题，为其串联溴结构域开发了大量高质量的化学探针。反过来，这些化学探针帮助揭示了 BET 溴结构域的深远生物学作用及其在疾病中的作用，最终导致了许多处于积极临床开发阶段的分子。然而，BET 亚家族仅代表已知人类溴结构域的 8/61，现在人们的注意力已经扩大到了其余 53 个非 BET 溴结构域的生物学作用。该研究领域的快速发展伴随着对有效溴结构域化学探针的要求的进一步了解，并导致了一些新的非 BET 溴结构域化学探针的开发。本文讨论了 2015 年 12 月以来的进展，突出了每个分子的优势/缺点，以及它们在验证非 BET 溴结构域作为可行的治疗靶点方面的价值。
