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Eur J Med Chem. 2017 Jan 5;125:696-709. doi: 10.1016/j.ejmech.2016.09.064. Epub 2016 Sep 22.

Exploration of the imidazo[1,2-b]pyridazine scaffold as a protein kinase inhibitor.

Author information

1
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France; Unité de Technologies Chimiques et Biologiques pour la Santé, Université Paris Descartes, UMR-S 1022 Inserm, 4 avenue de l'Observatoire, 75270 Paris cedex 06, France.
2
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France.
3
Institut Pasteur, Unité INSERM U1201, Département des Parasites et Insectes Vecteurs, Unité de Parasitologie Moléculaire et Signalisation, 28 rue du Dr. Roux, 75015 Paris, France.
4
Unité de Technologies Chimiques et Biologiques pour la Santé, Université Paris Descartes, UMR-S 1022 Inserm, 4 avenue de l'Observatoire, 75270 Paris cedex 06, France.
5
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France. Electronic address: meijer@manros-therapeutics.com.
6
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France. Electronic address: oumata@manros-therapeutics.com.

Abstract

3,6-Disubstituted imidazo[1,2-b]pyridazine derivatives were synthesized to identify new inhibitors of various eukaryotic kinases, including mammalian and protozoan kinases. Among the imidazo[1,2-b]pyridazines tested as kinase inhibitors, several derivatives were selective for DYRKs and CLKs, with IC50 < 100 nM. The characterization of the kinome of several parasites, such as Plasmodium and Leishmania, has pointed out profound divergences between protein kinases of the parasites and those of the host. This led us to investigate the activities of the prepared compounds against 11 parasitic kinases. 3,6-Disubstituted imidazo[1,2-b]pyridazines showed potent inhibition of Plasmodium falciparum CLK1 (PfCLK1). Compound 20a was found to be the most selective product against CLK1 (IC50 = 82 nM), CLK4 (IC50 = 44 nM), DYRK1A (IC50 = 50 nM), and PfCLK1 (IC50 = 32 nM). The compounds were also tested against Leishmania amazonensis. Several compounds showed anti-leishmanial activity at rather high (10 μM) concentration, but were not toxic at 1 μM or 10 μM, as judged by viability assays carried out using a neuroblastoma cell line.

KEYWORDS:

CLKs; Imidazo[1,2-b]pyridazine; Kinase inhibitor; Leishmania, DYRK1A; Unicellular parasites

PMID:
27721154
DOI:
10.1016/j.ejmech.2016.09.064
[Indexed for MEDLINE]

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