期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 236, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114369
关键词
Pyridoquinazolines; Kinase inhibition; Haspin
资金
- La Ligue Contre le Cancer/Comite du Cantal/Comite Grand-Ouest [29, 22, 56, 35, 45, 79]
- ITMO Cancer AVIESAN (National Alliance for Life Sciences & Health) within the framework of the Cancer Plan
- Auvergne Region (Jeune Chercheur Program)
- French Ministry of Higher Education and Research
- AbbVie [1097737]
- BayerAG [1097737]
- Boehringer Ingelheim [1097737]
- Canada Foundation for Innovation [1097737]
- Eshelman Institute for Innovation [1097737]
- Genentech [1097737]
- Genome Canada through Ontario Genomics Institute [1097737, OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond [1097737]
- Innovative Medicines Initiative 2 Joint Undertaking [1097737, 875510]
- Janssen [1097737]
- Merck KGaA [1097737]
- Merck Co [1097737]
- Pfizer [1097737]
- Takeda [1097737]
- Wellcome [1097737]
- German translational cancer network (DKTK)
- Frankfurt Cancer Institute (FCI)
Haspin is a potential target for the development of anticancer drugs, but current inhibitors show poor selectivity for human kinome. A new inhibitor with excellent activity and selectivity for Haspin has been identified, and its binding mode with Haspin has been determined through crystallography.
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. (c) 2022 Elsevier Masson SAS. All rights reserved.
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