Sundriyal Sandeep, Moniot Sébastien, Mahmud Zimam, Yao Shang, Di Fruscia Paolo, Reynolds Christopher R, Dexter David T, Sternberg Michael J E, Lam Eric W-F, Steegborn Clemens, Fuchter Matthew J
Department of Chemistry, Imperial College London , London SW7 2AZ, U.K.
Department of Biochemistry, University of Bayreuth , Universitaetsstrasse 30, 95447 Bayreuth, Germany.
J Med Chem. 2017 Mar 9;60(5):1928-1945. doi: 10.1021/acs.jmedchem.6b01690. Epub 2017 Feb 15.
Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a cocrystal structure of one of our compounds (29c) bound to SIRT2. This reveals our series to induce the formation of a previously reported selectivity pocket but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to an understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors.
沉默调节蛋白（SIRTs）是依赖烟酰胺腺嘌呤二核苷酸（NAD）的去酰基酶，已知参与多种病理生理过程，因此仍是有待进一步验证的有前景的治疗靶点。此前，我们报道了一种新型噻吩并嘧啶酮SIRT2抑制剂，对SIRT2具有良好的活性和出色的选择性。在此，我们报告了该化学系列的广泛构效关系（SAR）研究，并确定了支撑所观察到的优异活性的关键药效基团元素和理化性质。已鉴定出具有亚微摩尔级SIRT2抑制活性且对SIRT2亚型具有良好至优异选择性的新类似物。重要的是，我们报告了我们的一种化合物（29c）与SIRT2结合的共晶体结构。这表明我们的系列化合物可诱导形成先前报道的选择性口袋，但以与直观预期相反的方式结合。我们相信这些发现将极大地有助于理解SIRT2抑制剂的作用机制，并有助于鉴定优化的第二代抑制剂。
