Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, D-79104, Freiburg, Germany.
Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Str. 9, D-79104, Freiburg, Germany.
Eur J Med Chem. 2023 Mar 5;249:115139. doi: 10.1016/j.ejmech.2023.115139. Epub 2023 Jan 25.
For a long time, the development of bromodomain (BD) inhibitors (BDi) was almost exclusively related to the BET family. More recently, BDi for BDs outside the BET family have also been developed. Here we present a novel pan-BDi with micromolar affinities to various BDs, and nanomolar affinities to representatives of BD families I, II (Bromodomain and Extra-Terminal Domain (BET) family), III, and IV. The inhibitor shows a broad activity profile with nanomolar growth inhibition (GI50) values on various cancer cell lines. Subsequently, we were able to control the selectivity of the inhibitor by simple modifications and turned it into a highly selective BRD9 inhibitor.
长期以来，溴结构域（BD）抑制剂（BDi）的开发几乎完全与 BET 家族有关。最近，也开发了针对 BET 家族以外的 BD 的 BDi。在这里，我们展示了一种新型的泛 BD 抑制剂，对各种 BD 具有微摩尔亲和力，对 BD 家族 I、II（Bromodomain 和 Extra-Terminal Domain（BET）家族）、III 和 IV 的代表具有纳摩尔亲和力。该抑制剂在各种癌细胞系上表现出广泛的活性谱，具有纳摩尔级的生长抑制（GI50）值。随后，我们能够通过简单的修饰来控制抑制剂的选择性，并将其转化为高度选择性的 BRD9 抑制剂。
