title: New MKLP-2 inhibitors in the paprotrain series: Design, synthesis and biological evaluations.
abstract: Members of the kinesin superfamily are involved in key functions during intracellular transport and cell division. Their involvement in cell division makes certain kinesins potential targets for drug development in cancer chemotherapy. The two most advanced kinesin targets are Eg5 and CENP-E with inhibitors in clinical trials. Other mitotic kinesins are also being investigated for their potential as prospective drug targets. One recently identified novel potential cancer therapeutic target is the Mitotic kinesin-like protein 2 (MKLP-2), a member of the kinesin-6 family, which plays an essential role during cytokinesis. Previous studies have shown that inhibition of MKLP-2 leads to binucleated cells due to failure of cytokinesis. We have previously identified compound 1 (paprotrain) as the first selective inhibitor of MKLP-2. Herein we describe the synthesis and biological evaluation of new analogs of 1. Our structure-activity relationship (SAR) study reveals the key chemical elements in the paprotrain family necessary for MKLP-2 inhibition. We have successfully identified one MKLP-2 inhibitor 9a that is more potent than paprotrain. In addition, in vitro analysis of a panel of kinesins revealed that this compound is selective for MKLP-2 compared to other kinesins tested and also does not have an effect on microtubule dynamics. Upon testing in different cancer cell lines, we find that the more potent paprotrain analog is also more active than paprotrain in 10 different cancer cell lines. Increased selectivity and higher potency is therefore a step forward toward establishing MKLP-2 as a potential cancer drug target.
authors.affiliation: Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Labrière
authors.affiliation: School of Pharmacy, University College London, Department of Pharmaceutical and Biological Chemistry, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Talapatra
authors.affiliation: Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Thoret
authors.affiliation: Biokinesis S.A.S. 5, Rue de la Baume, 75008 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Bougeret
authors.affiliation: School of Pharmacy, University College London, Department of Pharmaceutical and Biological Chemistry, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Kozielski
authors.affiliation: Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France. Electronic address: catherine.guillou@cnrs.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guillou
mesh_terms: D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001923:Brain Chemistry; D045744:Cell Line, Tumor; D048749:Cytokinesis / Q000187:drug effects*; D015195:Drug Design; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D012756:Sheep; D013329:Structure-Activity Relationship
chemical_list: C555533:2-(1H-indol-3-yl)-3-(pyridin-3-yl)acrylonitrile; D050256:Antimitotic Agents; D007211:Indoles; C410089:KIF20A protein, human; D016547:Kinesins; D000181:Acrylonitrile
keywords: Cancer; Indole; MKLP-2 inhibitor; Mitotic kinesin; Paprotrain