title: Exploration of the imidazo[1,2-b]pyridazine scaffold as a protein kinase inhibitor.
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.
authors.affiliation: 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.
authors.forename: Lyamin Z
authors.initials: LZ
authors.lastname: Bendjeddou
authors.affiliation: ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Loaëc
authors.affiliation: ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Villiers
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Prina
authors.affiliation: 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.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Späth
authors.affiliation: 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.
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
authors.affiliation: ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France. Electronic address: meijer@manros-therapeutics.com.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France. Electronic address: oumata@manros-therapeutics.com.
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
mesh_terms: D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D056890:Eukaryota / Q000187:drug effects; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000977:Antiparasitic Agents; D047428:Protein Kinase Inhibitors; D011724:Pyridazines
keywords: CLKs; Imidazo[1,2-b]pyridazine; Kinase inhibitor; Leishmania, DYRK1A; Unicellular parasites