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Conception of DYRK1A kinase inhibitors via metal-catalyzed C–H arylation, inspired by fragment-growing studies
1 , 2 , 2 , 3 , 1 , * 4
1  Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen. CNRS, IRCOF, 1 Rue Tesnière, 76821 Mont St Aignan Cedex, France.
2  Université d’Orléans, ICOA, UMR CNRS 7311, BP 6759, 45067 Orléans Cedex 2, France
3  Manros Therapeutics, Perharidy Peninsula, 29680 Roscoff, France.
4  Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA UMR 6014, F-76000 Rouen, France

Published: 31 October 2018 by MDPI in 4th International Electronic Conference on Medicinal Chemistry session ECMC-4

The search for therapeutic inhibitors of specific kinases has been developed in the last three decades as a major approach to discover new drugs . Our group is focused on the regulation of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a conserved eukaryotic kinase that belongs to the DYRK family and the CMGC group, which includes cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK), and Ccd2-like kinases (CLKs). Five years ago, a series of tricyclic aminopyrimidine derivatives was synthesized and evaluated on DYRK1A and DYRK1B.

A fragment-growing approach was performed using a novel in silico tool that drills down through, to evaluate hundreds of thousands fragments extracted from co-crystallized kinase/inhibitor complexes. Addition of aromatic fragments on C2 seemed to increase the interaction with the hinge region.

Efficient metal catalyzed C–H arylation of 8-alkyl-thiazolo[5,4-f]-quinazolin-9-ones was explored for SAR studies. Application of this powerful chemical tool at the last stage of the synthesis of kinase inhibitors allowed the synthesis of arrays of molecules inspired by fragment-growing studies generated by molecular modeling calculations. Among the potentially active compounds designed through this strategy, FC162 (Cc) exhibits nanomolar IC50 values against some kinases, and is the best candidate for development as a DYRK kinase inhibitor.

Keywords: Thiazolo[5,4-f]quinazolin-9(8H)-ones; microwave-assisted synthesis; C–H arylation; protein kinases; DYRK1A; CDK5; GSK-3; CLK1; CK1