发现一种双重 SENP1 和 SENP2 抑制剂。
Discovery of a Dual SENP1 and SENP2 Inhibitor.
机构信息
Institute of Chemistry and Biotechnology, Competence Center for Drug Discovery, Zurich University of Applied Sciences (ZHAW), Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland.
出版信息
Int J Mol Sci. 2022 Oct 11;23(20):12085. doi: 10.3390/ijms232012085.
SUMOylation is a reversible post-translational modification (PTM) involving covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. Dysregulation of SUMOylation and deSUMOylation results in cellular malfunction and is linked to various diseases, such as cancer. Sentrin-specific proteases (SENPs) were identified for the maturation of SUMOs and the deconjugation of SUMOs from their substrate proteins. Hence, this is a promising target tackling the dysregulation of the SUMOylation process. Herein, we report the discovery of a novel protein-protein interaction (PPI) inhibitor for SENP1-SUMO1 by virtual screening and subsequent medicinal chemistry optimization of the hit molecule. The optimized inhibitor ZHAWOC8697 showed IC values of 8.6 μM against SENP1 and 2.3 μM against SENP2. With a photo affinity probe the SENP target was validated. This novel SENP inhibitor represents a new valuable tool for the study of SUMOylation processes and the SENP-associated development of small molecule-based treatment options.
SUMOylation 是一种可逆的翻译后修饰（PTM），涉及小泛素相关修饰物（SUMO）蛋白与底物蛋白的共价连接。SUMOylation 和去 SUMOylation 的失调导致细胞功能障碍，并与各种疾病相关，如癌症。Sentrin 特异性蛋白酶（SENPs）被鉴定用于 SUMO 的成熟和 SUMO 从其底物蛋白上的去共轭。因此，这是一个有前途的靶点，可以解决 SUMOylation 过程的失调。在此，我们通过虚拟筛选和随后对命中分子的药物化学优化，报告了一种新型 SENP1-SUMO1 蛋白-蛋白相互作用（PPI）抑制剂的发现。优化后的抑制剂 ZHAWOC8697 对 SENP1 的 IC 值为 8.6 μM，对 SENP2 的 IC 值为 2.3 μM。通过光亲和探针验证了 SENP 靶标。这种新型 SENP 抑制剂为 SUMOylation 过程的研究以及基于小分子的 SENP 相关治疗方法的发展提供了一种新的有价值的工具。
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