Leucettinibs, a Class of DYRK/CLK Kinase Inhibitors Inspired by the Marine Sponge Natural Product Leucettamine B

Dual-specificity,tyrosine phosphorylation-regulated kinases (DYRKs)and cdc2-like kinases (CLKs) recently attracted attention due to theircentral involvement in various pathologies. We here describe a familyof DYRK/CLK inhibitors derived from Leucettines and the marine naturalproduct Leucettamine B. Forty-five N2-functionalized2-aminoimidazolin-4-ones bearing a fused [6 + 5]-heteroarylmethylenewere synthesized. Benzothiazol-6-ylmethylene was selected as the mostpotent residue among 15 different heteroarylmethylenes. 186 N2-substituted 2-aminoimidazolin-4-ones bearing a benzothiazol-6-ylmethylene,collectively named Leucettinibs, were synthesized and extensivelycharacterized. Subnanomolar IC50 (0.5-20 nM on DYRK1A)inhibitors were identified and one Leucettinib was modeled in DYRK1Aand co-crystallized with CLK1 and the weaker inhibited off-targetCSNK2A1. Kinase-inactive isomers of Leucettinibs (>3-10 & mu;Mon DYRK1A), named iso-Leucettinibs, were synthesized and characterizedas suitable negative control compounds for functional experiments.Leucettinibs, but not iso-Leucettinibs, inhibit the phosphorylationof DYRK1A substrates in cells. Leucettinibs provide new research toolsand potential leads for further optimization toward therapeutic drugcandidates.