VTT-006, an anti-mitotic compound, binds to the Ndc80 complex and suppresses cancer cell growth in vitro .

Autor:	Laine LJ; VTT Health, VTT Technical Research Centre of Finland Ltd., Otaniemi, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland.; These authors contributed equally to this work., Mäki-Jouppila JHE; VTT Health, VTT Technical Research Centre of Finland Ltd., Otaniemi, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland.; Drug Research Doctoral Programme, University of Turku, Finland.; Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.; These authors contributed equally to this work., Kutvonen E; VTT Health, VTT Technical Research Centre of Finland Ltd., Otaniemi, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland., Tiikkainen P; VTT Health, VTT Technical Research Centre of Finland Ltd., Otaniemi, Finland., Nyholm TKM; Department of Biosciences, Åbo Akademi University, Turku, Finland., Tien JF; Department of Biochemistry, University of Washington, Seattle, WA, USA., Umbreit NT; Department of Biochemistry, University of Washington, Seattle, WA, USA., Härmä V; VTT Health, VTT Technical Research Centre of Finland Ltd., Otaniemi, Finland., Kallio L; VTT Health, VTT Technical Research Centre of Finland Ltd., Otaniemi, Finland., Davis TN; Department of Biochemistry, University of Washington, Seattle, WA, USA., Asbury CL; Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA., Poso A; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Gorbsky GJ; Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA., Kallio MJ; VTT Health, VTT Technical Research Centre of Finland Ltd., Otaniemi, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland.
Jazyk:	angličtina
Zdroj:	Oncoscience [Oncoscience] 2021 Dec 10; Vol. 8, pp. 134-153. Date of Electronic Publication: 2021 Dec 10 (Print Publication: 2021).
DOI:	10.18632/oncoscience.549
Abstrakt:	Hec1 (Highly expressed in cancer 1) resides in the outer kinetochore where it works to facilitate proper kinetochore-microtubule interactions during mitosis. Hec1 is overexpressed in various cancers and its expression shows correlation with high tumour grade and poor patient prognosis. Chemical perturbation of Hec1 is anticipated to impair kinetochore-microtubule binding, activate the spindle assembly checkpoint (spindle checkpoint) and thereby suppress cell proliferation. In this study, we performed high-throughput screen to identify novel small molecules that target the Hec1 calponin homology domain (CHD), which is needed for normal microtubule attachments. 4 million compounds were first virtually fitted against the CHD, and the best hit molecules were evaluated in vitro . These approaches led to the identification of VTT-006, a 1,2-disubstituted-tetrahydro-beta-carboline derivative, which showed binding to recombinant Ndc80 complex and modulated Hec1 association with microtubules in vitro . VTT-006 treatment resulted in chromosome congression defects, reduced chromosome oscillations and induced loss of inter-kinetochore tension. Cells remained arrested in mitosis with an active spindle checkpoint for several hours before undergoing cell death. VTT-006 suppressed the growth of several cancer cell lines and enhanced the sensitivity of HeLa cells to Taxol. Our findings propose that VTT-006 is a potential anti-mitotic compound that disrupts M phase, impairs kinetochore-microtubule interactions, and activates the spindle checkpoint. Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.
Databáze:	MEDLINE
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