An Unusual Binding Model of the Methyl 9-Anilinothiazolo[5,4-f] quinazoline-2-carbimidates (EHT 1610 and EHT 5372) Confers High Selectivity for Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases

Abstract

Methyl 9-anilinothiazolo[5,4-f]quinazoline-2-carbimidates 1 (EHT 5372) and 2 (EHT 1610) are strong inhibitors of DYRK's family kinases. The crystal structures of the complex revealed a noncanonical binding mode of compounds 1 and 2 in DYRK2, explaining the remarkable selectivity and potency of these inhibitors. The structural data and comparison presented here provide therefore a template for further improvement of this inhibitor class and for the development of novel inhibitors selectively targeting DYRK kinases.

Design of new disubstituted imidazo[1,2-b]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation

“…The difference of activity between CHR-6494 5 and inhibitor 21 towards DYRK1A could be explained by the lack of one hydrogen bond acceptor or a lack of one salt bridge, since the position of Asp611 in Haspin corresponds to asparagine Asn234 in DYRK1A. Moreover, the NH 2 side chain of Asn234 may be exposed to the protonated nitrogen, thus forming an unfavourable interaction 43 .…”

Biological Characterization of 8-Cyclopropyl-2-(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one, a Promising Inhibitor of DYRK1A

“…In the last 15 years, more than 40 kinases inhibitors have been approved by the US and Food and Drug Administration (FDA), mainly for cancer indications [10,11]. In the same period, our group has been dedicated to the conception and synthesis of bioactive heterocycles that can modulate the activity of deregulated kinases (Figure 1) [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27], with a particular focus on dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) which play a role in the development of diseases such as cancer, Alzheimer's disease (AD) and Down syndrome (DS) [28,29]. Figure 1.…”

“…Summary of some of the compounds that have been identified by our group. (a) CDKs and GSK3 inhibitors [12,13]; (b) CK1 and CLK1 inhibitors [14][15][16]; (c) DYRKs inhibitors [17][18][19][20][21][22][23][24].…”

Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design

“…The methyl 9-anilinothiazolo[5,4- f ]quinazoline-2-carbimidate EHT 5372 ( 4 ) ( Figure 1 ) inhibits DYRK1A and DYRK1B at subnanomolar concentrations (IC 50 DYRK1A 0.22 nM; IC 50 DYRK1B 0.28 nM). Compound 4 and closely related structures represent the most potent DYRK1A inhibitors reported so far, with striking selectivity even compared to closely related kinases of the CMGC group [ 27 , 28 , 29 ]. EHT 5372 also inhibits cellular DYRK1A-mediated tau phosphorylation and Aβ production, albeit with significantly lower potency (IC 50 1.06–1.17 µM) [ 30 ].…”