Abstract 4140: Identification of a selective MKLP2/KIF20A inhibitor with high in-vivo antitumor activity

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 13_Supplement; p. 4140
• Main Authors: Collette, Yves, Miserey-Lenkei, Stephanie, Guillou, Catherine, Carniato, Denis, Pau, Bernard, Goud, Bruno, Vey, Norbert, Bougeret, Cecile E.
• Format: Journal Article
• Language: English
• Published: 01.07.2017
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-4140

Abstract Mitotic kinesins are essential regulators of cancer cell replication and migration. The mitotic kinesin MKLP2/KIF20A, a member of the kinesin-6 family, plays an essential role during cytokinesis and was identified as a potential new target for cancer chemotherapy1. We have previously identified Paprotrain, a new synthetic compound, as the first selective MKLP2 inhibitor2. Recently, we obtained Paprotrain analogues with higher potency on MKLP23. Herein we describe the identification and characterization of BKS0349, a new potent analogue of Paprotrain. BKS0349 compound is 10 times more potent than paprotain on MKLP2 inhibition and has shown an even more restricted specificity profile when tested on a large set of kinases. In-vitro this compound is highly cytotoxic on a wide panel of human cancer cell lines (IC50 ranged 10-70 nM, which corresponds to 1000 fold improvement of paprotrain potency) while no toxicity is observed on human normal cells such as peripheral blood mononuclear cells (PBMC) and primary hepatocytes (IC50 >50µM). BKS0349 compound is well tolerated in mice using repeated intravenous administrations (200 mg/kg, twice a week for 4 weeks). In xenografted nude mice, in-vivo treatment with BKS0349 compound demonstrates a high antitumor activity against various human cancer cell models, either sensitive or resistant to some standard-of-care treatments. In addition, human cancer cells treated in-vitro as well as in-vivo with BSK0349 compound display Golgi scattering and a mitotic arrest leading to cell death, as hallmarks of BKS0349’ mode of action. These findings show that MKLP2 is a potential new target for cancer chemotherapy and BKS0349 a good candidate to be developed for cancer treatment. 1Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance. P. Khongkow et al. Oncogene, 2015, 1-13. 2Relocation of Aurora B and Survivin from centromeres to the central spindle impaired by a kinesin-specific MKLP-2 inhibitor. S. Tcherniuk et al. Angew. Chem. Int. Ed., 2010, 49:8228-8231. 3New MKLP-2 inhibitors in the paprotrain series: design, synthesis and biological evaluations. C. Labrière et al. Bioorg and Med Chem, 2016, 24:731-734. Note: This abstract was not presented at the meeting. Citation Format: Yves Collette, Stephanie Miserey-Lenkei, Catherine Guillou, Denis Carniato, Bernard Pau, Bruno Goud, Norbert Vey, Cecile E. Bougeret. Identification of a selective MKLP2/KIF20A inhibitor with high in-vivo antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4140. doi:10.1158/1538-7445.AM2017-4140