NMS-1286937 is an orally active small-molecule compound. NMS-1286937 potently and selectively inhibits Polo-like kinase 1 (PLK1) activity with a half-maximal inhibitory concentration (IC50) of 2nM[1]. By competitively binding to the ATP site, NMS-1286937 reversibly inhibits PLK1, leading to G2/M phase cell cycle arrest, chromosomal misalignment, and abnormal spindle formation in various tumor cells, ultimately resulting in apoptosis[2]. NMS-1286937 shows potential in the treatment of solid tumors and hematological malignancies[3-4].
In vitro, treatment of medulloblastoma cell lines (D425, D458) with NMS-1286937 (10–20nM) for 24–48 hours induced G2/M phase cell cycle arrest and significantly inhibited cell proliferation and stem cell self-renewal capacity[5]. In ovarian cancer cell lines (Ovcar-3, ES-2), treatment with NMS-1286937 (30–50nM) for 24–72 hours suppressed cell proliferation while activating apoptosis and DNA damage pathways[6].
In vivo, daily oral administration of NMS-1286937 (25mg/kg) for four weeks in LKB1fl/fl p53fl/fl transgenic endometrial cancer model mice significantly inhibited tumor growth and reduced tumor weight[7]. In nude mice bearing patient-derived xenografts (PDX) of platinum-resistant ovarian cancer, once-weekly intravenous administration of NMS-1286937 (50mg/kg) in combination with Paclitaxel (15mg/kg) significantly extended median survival and induced mitotic arrest and DNA damage in tumor tissues[8].
References:
[1] Valsasina B, Beria I, Alli C, et al. NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. Mol Cancer Ther. 2012 Apr;11(4):1006-16.
[2] Su S, Chhabra G, Singh CK, et al. PLK1 inhibition-based combination therapies for cancer management. Transl Oncol. 2022 Feb;16:101332.
[3] Ahn DH, Barzi A, Ridinger M, et al. Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Phase Ib Clinical Study. Clin Cancer Res. 2024 May 15;30(10):2039-2047.
[4] Nouri M, Varkaris A, Ridinger M, et al. AKT Inhibition Sensitizes to Polo-Like Kinase 1 Inhibitor Onvansertib in Prostate Cancer. Mol Cancer Ther. 2024 Oct 1;23(10):1404-1417.
[5] Wang D, Veo B, Pierce A, et al. A novel PLK1 inhibitor onvansertib effectively sensitizes MYC-driven medulloblastoma to radiotherapy. Neuro Oncol. 2022 Mar 12;24(3):414-426.
[6] Chiappa M, Decio A, Guarrera L, et al. Onvansertib treatment overcomes olaparib resistance in high-grade ovarian carcinomas. Cell Death Dis. 2024 Jul 22;15(7):521.
[7] Sinha N, Shen X, Haag J, et al. Onvansertib exhibits anti-proliferative and anti-invasive effects in endometrial cancer. Front Pharmacol. 2025 Mar 17;16:1545038.
[8] Affatato R, Chiappa M, Guffanti F, et al. Onvansertib and paclitaxel combined in platinum-resistant ovarian carcinomas. Ther Adv Med Oncol. 2022 May 31;14:17588359221095064.