Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes.
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Authors
Saint-Dizier, F
Matthews, TP
Gregson, AM
Prevet, H
McHardy, T
Colombano, G
Saville, H
Rowlands, M
Ewens, C
McAndrew, PC
Tomlin, K
Guillotin, D
Mak, GW-Y
Drosopoulos, K
Poursaitidis, I
Burke, R
van Montfort, R
Linardopoulos, S
Collins, I
Matthews, TP
Gregson, AM
Prevet, H
McHardy, T
Colombano, G
Saville, H
Rowlands, M
Ewens, C
McAndrew, PC
Tomlin, K
Guillotin, D
Mak, GW-Y
Drosopoulos, K
Poursaitidis, I
Burke, R
van Montfort, R
Linardopoulos, S
Collins, I
Document Type
Journal Article
Date
2023-02-23
Date Accepted
2023-02-07
Abstract
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.
Citation
Journal of Medicinal Chemistry, 2023, 66 (4), pp. 2622 - 2645
Source Title
Journal of Medicinal Chemistry
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
1520-4804
1520-4804
Collections
Research Team
Medicinal Chemistry 3
Hit Discov Struct Design
Hit Discov Struct Design