2. Academic Validation
  3. Synthesis and biological evaluation of Haspin inhibitors: Kinase inhibitory potency and cellular activity

Synthesis and biological evaluation of Haspin inhibitors: Kinase inhibitory potency and cellular activity

  • Eur J Med Chem. 2022 Jun 5;236:114369. doi: 10.1016/j.ejmech.2022.114369.
Wael Zeinyeh 1,  Yannick J Esvan 1,  Béatrice Josselin 2,  Mathilde Defois 1,  Blandine Baratte 2,  Stefan Knapp 3,  Apirat Chaikuad 3,  Fabrice Anizon 1,  Francis Giraud 4,  Sandrine Ruchaud 5,  Pascale Moreau 6
Affiliations

Affiliations

  • 1 Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000, Clermont-Ferrand, France.
  • 2 Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France; Sorbonne Université, CNRS, FR2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, 29680, Roscoff, France.
  • 3 Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany; Buchmann Institute for Molecular Life Sciences, Structural Genomics Consortium (SGC), Max-von-Laue-Str. 15, 60438, Frankfurt am Main, Germany.
  • 4 Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000, Clermont-Ferrand, France. Electronic address: francis.giraud@uca.fr.
  • 5 Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France. Electronic address: sandrine.ruchaud@sb-roscoff.fr.
  • 6 Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000, Clermont-Ferrand, France. Electronic address: pascale.moreau@uca.fr.
PMID: 35447555 DOI: 10.1016/j.ejmech.2022.114369
Abstract

Haspin (haploid germ cell-specific nuclear protein kinase) offers a potential target for the development of new Anticancer drugs. Thus, the identification of new inhibitors targeting this protein kinase is of high interest. However, Haspin inhibitors developed to date show a poor selectivity profile over other protein kinases of the human kinome. Here, we identified a new pyridoquinazoline based inhibitor (4), with excellent inhibitory activity and selectivity for Haspin (IC50 of 50 nM). We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or Cancer cell lines. In addition, we determined the binding mode of analog 2a in complex with Haspin using X-ray crystallography.

Keywords

Haspin; Kinase inhibition; Pyridoquinazolines.

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