Department of Biochemistry, University of Bayreuth, Universitaetsstr. 30, 95447, Bayreuth, Germany.
Los Alamos National Laboratory, 87544, Los Alamos, NM, USA.
ChemMedChem. 2024 Oct 16;19(20):e202400273. doi: 10.1002/cmdc.202400273. Epub 2024 Aug 19.
Sirtuin 6 (Sirt6), an NAD-dependent deacylase, has emerged as a promising target for aging-related diseases and cancer. Advancing the medicinal chemistry of Sirt6 modulators is crucial for the development of chemical probes aimed at unraveling the intricate biological functions of Sirt6 and unlocking its therapeutic potential. A proprietary DNA-encoded library yielded Sirt6 inhibitor 2-Pr, displaying remarkable inhibitory activity and isoform-selectivity, and featuring a chemical structure distinct from reported Sirt6 modulators. In this study, we explore the inhibitory mechanism of 2-Pr, evaluating the impact of chemical modifications and presenting a crystal structure of the Sirt6/ADP-ribose/2-Pr complex. Notably, co-crystal structure analysis reveals an unexpected and unprecedented binding mode of Sirt6, with 2-Pr spanning the acyl channel of the enzyme, extending into the acetyl-lysine binding pocket, and reaching toward the C-site. This unique binding mode guides potential avenues for developing potent and selective Sirt6 inhibitors.
Sirtuin 6 (Sirt6)，一种 NAD 依赖性脱酰酶，已成为与衰老相关疾病和癌症的有希望的靶点。推进 Sirt6 调节剂的药物化学研究对于开发旨在揭示 Sirt6 复杂生物学功能并释放其治疗潜力的化学探针至关重要。专有 DNA 编码文库产生了 Sirt6 抑制剂 2-Pr，其表现出显著的抑制活性和同工酶选择性，并且其化学结构与报道的 Sirt6 调节剂不同。在这项研究中，我们探讨了 2-Pr 的抑制机制，评估了化学修饰的影响，并提出了 Sirt6/ADP-ribose/2-Pr 复合物的晶体结构。值得注意的是，共晶结构分析揭示了 Sirt6 的一种出乎意料且前所未有的结合模式，其中 2-Pr 跨越酶的酰基通道，延伸到乙酰-赖氨酸结合口袋，并朝向 C 位延伸。这种独特的结合模式为开发有效和选择性的 Sirt6 抑制剂提供了潜在途径。
