Discovery of Natural Ursane-type SENP1 Inhibitors and the Platinum Resistance Reversal Activity Against Human Ovarian Cancer Cells: A Structure-Activity Relationship Study.

Abstract	Platinum-resistant ovarian cancer is one of the most common and refractory gynecologic cancers around the world. The SENP1/JAK2 (small ubiquitin-like modifier-specific protease 1/Janus activating kinase 2) axis activation has been proposed as a critical mechanism in platinum-resistant ovarian cancer, and as such, SENP1 inhibitors become a feasible alternative to reverse platinum resistance. In this work, 29 commercially available natural ursane-type aglycones were tested for their SENP1 inhibitory activities, among which 12 aglycones showed IC50 activity at the concentration below 5 μM. Pomolic acid and tormentic acid were identified as potent SENP1 inhibitors with the IC50 values of 5.1 and 4.3 μM, respectively. The structure-activity relationship (SAR) of ursane-type SENP1 inhibitors was evaluated. A molecular docking model of the SENP1-tormentic acid complex was obtained and applied to describe the SAR. Moreover, the combinations of cisplatin with pomolic acid (IC50 = 3.69 μM, combination index (CI) = 0.23) and tormentic acid (IC50 = 2.40 μM, CI = 0.30) exhibited potent platinum-resistant reversal activities to cisplatin only (IC50 = 28.23 μM) against the human ovarian cancer SKOV3 cells. The data suggested a potential for pomolic acid and tormentic acid to be promising compounds for in vivo studies of platinum-resistant ovarian cancer with SENP1 activation.
Authors	Huiqiang Wei, Jianghong Guo, Xiao Sun, Wenfeng Gou, Hongxin Ning, Haihua Shang, Qiang Liu, Wenbin Hou, Yiliang Li
Journal	Journal of natural products (J Nat Prod) Vol. 85 Issue 5 Pg. 1248-1255 (05 27 2022) ISSN: 1520-6025 [Electronic] United States
PMID	35500202 (Publication Type: Journal Article, Review, Research Support, Non-U.S. Gov't)
Chemical References	Triterpenes ursane SENP1 protein, human Cysteine Endopeptidases Cisplatin
Topics	Carcinoma, Ovarian Epithelial Cell Line, Tumor Cisplatin (pharmacology) Cysteine Endopeptidases Drug Resistance, Neoplasm Female Humans Molecular Docking Simulation Ovarian Neoplasms (drug therapy) Structure-Activity Relationship Triterpenes

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