ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles

Varování

Publikace nespadá pod Lékařskou fakultu, ale pod Přírodovědeckou fakultu. Oficiální stránka publikace je na webu muni.cz.

Autoři	ŘEZNÍČKOVÁ Eva TENORA Lukáš POSPÍŠILOVÁ Pavlína GALETA Juraj JORDA Radek BERKA Karel MAJER Pavel POTÁČEK Milan KRYŠTOF Vladimír
Rok publikování	2017
Druh	Článek v odborném periodiku
Časopis / Zdroj	European Journal of Medicinal Chemistry
Fakulta / Pracoviště MU	Přírodovědecká fakulta
Citace
www	http://dx.doi.org/10.1016/j.ejmech.2017.01.018
Doi	http://dx.doi.org/10.1016/j.ejmech.2017.01.018
Obor	Organická chemie
Klíčová slova	Transforming growth factor beta receptor I; Protein kinase; Inhibitor; Substituted pyrrolo[1.2-b]pyrazoles
Popis	A series of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles (DPPs) was synthesized and evaluated for their ALK5 inhibition activity. The most potent compounds displayed submicromolar IC50 values for ALK5. Preliminary profiling of one of the most active compounds in a panel of 50 protein kinases revealed its selectivity for ALK5. In cells, the compounds caused dose-dependent dephosphorylation of SMAD2, a well-established substrate of ALK5. In addition, the compounds blocked translocation of SMAD2/3 to nuclei of cells stimulated with TGFb and the protein remained predominantly in cytoplasm, further confirming their molecular target. Therefore, novel DPP derivatives proved to be active as ALK5 inhibitors.
Související projekty:	Česká národní infrastruktura pro biologická data