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Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes

[Image: see text] The existence of multiple centrosomes in some cancer cells can lead to cell death through the formation of multipolar mitotic spindles and consequent aberrant cell division. Many cancer cells rely on HSET (KIFC1) to cluster the extra centrosomes into two groups to mimic the bipolar...

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Autores principales: Saint-Dizier, François, Matthews, Thomas P., Gregson, Aaron M., Prevet, Hugues, McHardy, Tatiana, Colombano, Giampiero, Saville, Harry, Rowlands, Martin, Ewens, Caroline, McAndrew, P. Craig, Tomlin, Kathy, Guillotin, Delphine, Mak, Grace Wing-Yan, Drosopoulos, Konstantinos, Poursaitidis, Ioannis, Burke, Rosemary, van Montfort, Rob, Linardopoulos, Spiros, Collins, Ian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9969401/
https://www.ncbi.nlm.nih.gov/pubmed/36749938
http://dx.doi.org/10.1021/acs.jmedchem.2c01591
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author Saint-Dizier, François
Matthews, Thomas P.
Gregson, Aaron M.
Prevet, Hugues
McHardy, Tatiana
Colombano, Giampiero
Saville, Harry
Rowlands, Martin
Ewens, Caroline
McAndrew, P. Craig
Tomlin, Kathy
Guillotin, Delphine
Mak, Grace Wing-Yan
Drosopoulos, Konstantinos
Poursaitidis, Ioannis
Burke, Rosemary
van Montfort, Rob
Linardopoulos, Spiros
Collins, Ian
author_facet Saint-Dizier, François
Matthews, Thomas P.
Gregson, Aaron M.
Prevet, Hugues
McHardy, Tatiana
Colombano, Giampiero
Saville, Harry
Rowlands, Martin
Ewens, Caroline
McAndrew, P. Craig
Tomlin, Kathy
Guillotin, Delphine
Mak, Grace Wing-Yan
Drosopoulos, Konstantinos
Poursaitidis, Ioannis
Burke, Rosemary
van Montfort, Rob
Linardopoulos, Spiros
Collins, Ian
author_sort Saint-Dizier, François
collection PubMed
description [Image: see text] The existence of multiple centrosomes in some cancer cells can lead to cell death through the formation of multipolar mitotic spindles and consequent aberrant cell division. Many cancer cells rely on HSET (KIFC1) to cluster the extra centrosomes into two groups to mimic the bipolar spindle formation of non-centrosome-amplified cells and ensure their survival. Here, we report the discovery of a novel 2-(3-benzamidopropanamido)thiazole-5-carboxylate with micromolar in vitro inhibition of HSET (KIFC1) through high-throughput screening and its progression to ATP-competitive compounds with nanomolar biochemical potency and high selectivity against the opposing mitotic kinesin Eg5. Induction of the multipolar phenotype was shown in centrosome-amplified human cancer cells treated with these inhibitors. In addition, a suitable linker position was identified to allow the synthesis of both fluorescent- and trans-cyclooctene (TCO)-tagged probes, which demonstrated direct compound binding to the HSET protein and confirmed target engagement in cells, through a click-chemistry approach.
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spelling pubmed-99694012023-02-28 Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes Saint-Dizier, François Matthews, Thomas P. Gregson, Aaron M. Prevet, Hugues McHardy, Tatiana Colombano, Giampiero Saville, Harry Rowlands, Martin Ewens, Caroline McAndrew, P. Craig Tomlin, Kathy Guillotin, Delphine Mak, Grace Wing-Yan Drosopoulos, Konstantinos Poursaitidis, Ioannis Burke, Rosemary van Montfort, Rob Linardopoulos, Spiros Collins, Ian J Med Chem [Image: see text] The existence of multiple centrosomes in some cancer cells can lead to cell death through the formation of multipolar mitotic spindles and consequent aberrant cell division. Many cancer cells rely on HSET (KIFC1) to cluster the extra centrosomes into two groups to mimic the bipolar spindle formation of non-centrosome-amplified cells and ensure their survival. Here, we report the discovery of a novel 2-(3-benzamidopropanamido)thiazole-5-carboxylate with micromolar in vitro inhibition of HSET (KIFC1) through high-throughput screening and its progression to ATP-competitive compounds with nanomolar biochemical potency and high selectivity against the opposing mitotic kinesin Eg5. Induction of the multipolar phenotype was shown in centrosome-amplified human cancer cells treated with these inhibitors. In addition, a suitable linker position was identified to allow the synthesis of both fluorescent- and trans-cyclooctene (TCO)-tagged probes, which demonstrated direct compound binding to the HSET protein and confirmed target engagement in cells, through a click-chemistry approach. American Chemical Society 2023-02-07 /pmc/articles/PMC9969401/ /pubmed/36749938 http://dx.doi.org/10.1021/acs.jmedchem.2c01591 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Saint-Dizier, François
Matthews, Thomas P.
Gregson, Aaron M.
Prevet, Hugues
McHardy, Tatiana
Colombano, Giampiero
Saville, Harry
Rowlands, Martin
Ewens, Caroline
McAndrew, P. Craig
Tomlin, Kathy
Guillotin, Delphine
Mak, Grace Wing-Yan
Drosopoulos, Konstantinos
Poursaitidis, Ioannis
Burke, Rosemary
van Montfort, Rob
Linardopoulos, Spiros
Collins, Ian
Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes
title Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes
title_full Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes
title_fullStr Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes
title_full_unstemmed Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes
title_short Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes
title_sort discovery of 2-(3-benzamidopropanamido)thiazole-5-carboxylate inhibitors of the kinesin hset (kifc1) and the development of cellular target engagement probes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9969401/
https://www.ncbi.nlm.nih.gov/pubmed/36749938
http://dx.doi.org/10.1021/acs.jmedchem.2c01591
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