Abstract 3048: <i>In vitro</i> and <i>in vivo</i> anti-cancer properties of novel synthetic inhibitor targeting human NAD(P) dependent steroid dehydrogenase-like

Background: NAD(P)-Dependent Steroid Dehydrogenase-Like (NSDHL), which is involved in cholesterol synthesis, has been found to play a role in breast cancer stemness, growth, and metastasis. NSDHL is emerging as a potential new therapeutic target for breast cancer. This aim is to evaluate molecular mechanisms underlying the anti-cancer properties of a novel NSDHL inhibitor in breast cancer models in vitro and in vivo. Methods: A structure-based inhibitor of NSDHL (Compound 9) was developed by Dr. Lee Bong-Jin. Compound 9 (1-250 μM) was treated in diverse human breast cancer cell lines ( MCF-7, ZR75-1, BT474, BT-20, MDA-MB-231) for 2-7 days and administered by oral gavage (2.5 mg/kg/day) for 30 days in an orthotropic breast tumor model of BALB/c Nude mouse. Anti-cancer activities and molecular mechanisms of Compound 9 were evaluated by cell cycle analysis using DNA staining with PI, apoptosis analysis using annexin V/PI-labeling, cell proliferation analysis using crystal violet assay, cell migration analysis using transwell migration assay, western blot, immunohistochemistry, and TEM image. Result: Rhodamine B-conjugated Compound-9 was easily internalized into breast cancer cells within an hour. Compound 9 exerted anti-proliferative and anti-migratory activity, G0/G1 phase arrest, and apoptotic and autophagic death along with the downregulation of XIAP and BCL2, the upregulation of P62 and LC3II, and modulation of the Akt/mTOR/MAPK signaling pathway. A combination of Compound 9 and paclitaxel enhanced the anticancer activity of paclitaxel in cultured breast cancer cells. Compound-9, when given orally to mice, inhibited the breast tumor growth without affecting their body weight. Conclusions: We suggest that Compound 9 can be employed as a potential therapeutic drug to target NSDHL in cancer as well as cholesterol-related diseases. Citation Format: Hoe Suk Kim, So-Hyun Yoon Yoon, Sangeun Lee, Seungyeon Ryu, Han-Byoel Lee, Bong-Jin Lee, Wonshik Han. In vitro and in vivo anti-cancer properties of novel synthetic inhibitor targeting human NAD(P) dependent steroid dehydrogenase-like [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3048.