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

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.