Zhang Yuzhao, Xiong Meijun, Chen Zixin, Seabra Gustavo, Liu Jun, Li Chenglong, Cui Lina
Department of Medicinal Chemistry, College of Pharmacy, UF Health Science Center, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610, United States.
ACS Med Chem Lett. 2024 May 23;15(7):1032-1040. doi: 10.1021/acsmedchemlett.3c00268. eCollection 2024 Jul 11.
Heparanase (HPSE) is an enzyme that cleaves heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs). Overexpression of HPSE is associated with various types of cancer, inflammation, and immune disorders, making it a highly promising therapeutic target. Previously developed HPSE inhibitors that have advanced to clinical trials are polysaccharide-derived compounds or their mimetics; however, these molecules tend to suffer from poor bioavailability, side effects via targeting other saccharide binding proteins, and heterogeneity. Few small-molecule inhibitors have progressed to the preclinical or clinical stages, leaving a gap in HPSE drug discovery. In this study, a novel small molecule that can inhibit HPSE activity was discovered through high-throughput screening (HTS) using an ultrasensitive HPSE probe. Computational tools were employed to elucidate the mechanisms of inhibition. The essential structural features of the hit compound were summarized into a structure-activity relationship (SAR) theory, providing insights into the future design of HPSE small-molecule inhibitors.
乙酰肝素酶（HPSE）是一种从硫酸乙酰肝素蛋白聚糖（HSPGs）上切割硫酸乙酰肝素（HS）侧链的酶。HPSE的过表达与多种类型的癌症、炎症和免疫紊乱相关，这使其成为一个极具前景的治疗靶点。先前已进入临床试验的HPSE抑制剂是多糖衍生化合物或其模拟物；然而，这些分子往往存在生物利用度差、通过靶向其他糖结合蛋白产生副作用以及异质性等问题。很少有小分子抑制剂进入临床前或临床阶段，这在HPSE药物研发方面留下了空白。在本研究中，通过使用超灵敏HPSE探针的高通量筛选（HTS）发现了一种能够抑制HPSE活性的新型小分子。利用计算工具阐明抑制机制。将命中化合物的基本结构特征总结为构效关系（SAR）理论，为HPSE小分子抑制剂的未来设计提供了见解。
