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

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

  • Eur J Med Chem. 2017 Feb 15:127:632-642. doi: 10.1016/j.ejmech.2017.01.018.
Eva Řezníčková 1,  Lukáš Tenora 2,  Pavlína Pospíšilová 1,  Juraj Galeta 2,  Radek Jorda 1,  Karel Berka 3,  Pavel Majer 4,  Milan Potáček 2,  Vladimír Kryštof 5
Affiliations

Affiliations

  • 1 Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 783 71 Olomouc, Czech Republic.
  • 2 Department of Chemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic.
  • 3 Department of Physical Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, 17. listopadu 12, 771 46 Olomouc, Czech Republic.
  • 4 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague, Czech Republic.
  • 5 Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 783 71 Olomouc, Czech Republic. Electronic address: vladimir.krystof@upol.cz.
PMID: 28135685 DOI: 10.1016/j.ejmech.2017.01.018
Abstract

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 TGFβ and the protein remained predominantly in cytoplasm, further confirming their molecular target. Therefore, novel DPP derivatives proved to be active as ALK5 inhibitors.

Keywords

Inhibitor; Protein kinase; Substituted pyrrolo[1,2-b]pyrazoles; Transforming growth factor beta receptor I.

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