鉴定高效且选择性的 HTRA1 抑制剂。
Identification of highly potent and selective HTRA1 inhibitors.
机构信息
Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, CA 94305, USA; Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, CA 94304, USA.
Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, CA 94304, USA.
出版信息
Bioorg Med Chem Lett. 2024 Sep 1;109:129814. doi: 10.1016/j.bmcl.2024.129814. Epub 2024 May 28.
High temperature requirement A serine peptidase 1 (HTRA1) is a serine protease involved in an array of signaling pathways. It is also responsible for the regulation of protein aggregates via refolding, translocation, and degradation. It has subsequently been found that runaway proteolytic HTRA1 activity plays a role in a variety of diseases, including Age-Related Macular Degeneration (AMD), osteoarthritis, and Rheumatoid Arthritis. Selective inhibition of serine protease HTRA1 therefore offers a promising new strategy for the treatment of these diseases. Herein we disclose structure-activity-relationship (SAR) studies which identify key interactions responsible for binding affinity of small molecule inhibitors to HTRA1. The study results in highly potent molecules with IC's less than 15 nM and excellent selectivity following a screen of 35 proteases.
高温需求 A 丝氨酸肽酶 1（HTRA1）是一种参与多种信号通路的丝氨酸蛋白酶。它还负责通过重折叠、易位和降解来调节蛋白质聚集体。随后发现，失控的蛋白水解 HTRA1 活性在多种疾病中起作用，包括年龄相关性黄斑变性（AMD）、骨关节炎和类风湿性关节炎。因此，选择性抑制丝氨酸蛋白酶 HTRA1 为这些疾病的治疗提供了一种有前途的新策略。在此，我们披露了结构-活性关系（SAR）研究，这些研究确定了小分子抑制剂与 HTRA1 结合亲和力的关键相互作用。该研究结果得到了高度有效的分子，其 IC50 小于 15 nM，在对 35 种蛋白酶进行筛选后具有优异的选择性。
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