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

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

  • J Med Chem. 2023 Feb 23;66(4):2622-2645. doi: 10.1021/acs.jmedchem.2c01591.
François Saint-Dizier 1,  Thomas P Matthews 1,  Aaron M Gregson 1,  Hugues Prevet 1,  Tatiana McHardy 1,  Giampiero Colombano 1,  Harry Saville 1,  Martin Rowlands 1,  Caroline Ewens 1,  P Craig McAndrew 1,  Kathy Tomlin 1,  Delphine Guillotin 1,  Grace Wing-Yan Mak 1,  Konstantinos Drosopoulos 2,  Ioannis Poursaitidis 1,  Rosemary Burke 1,  Rob van Montfort 1 3,  Spiros Linardopoulos 1 2,  Ian Collins 1
Affiliations

Affiliations

  • 1 Centre for Cancer Drug Discovery, Division of Cancer Therapeutics, The Institute of Cancer Research, London SW7 3RP, U.K.
  • 2 Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW7 3RP, U.K.
  • 3 Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, U.K.
PMID: 36749938 DOI: 10.1021/acs.jmedchem.2c01591
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.

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