Chemical, Biochemical, Cellular, and Physiological Characterization of Leucettinib-21, a Down Syndrome and Alzheimer’s Disease Drug Candidate

Discovery of ZJCK-6-46: A Potent, Selective, and Orally Available Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor for the Treatment of Alzheimer’s Disease

“…Furthermore, compound 32 also inhibited the activities of CLKs, especially, CLK1 and CLK4 (IC 50 = 1.68 and 1.80 nM, respectively), while CLK3 showed relatively less sensitiveness (IC 50 = 38.91 nM). Indeed, it seemed to be foreseeable that compound 32 might exhibit excellent inhibitory potency for DYRKs and CLKs according to previous reports on DYRK1A inhibitors. ,,,− Fortunately, compound 32 showed moderate selectivity for other DYRK isoforms except for DYRK1B, while its potential off-target risk from strong inhibition of especially CLK1 and CLK4 could not be ignored. This also indicated that current structural optimization might not be sufficient to overcome the difficulty of the compound still being able to significantly inhibit the activity of the closely related CLKs.…”

Efficacy of DYRK1A inhibitors in novel models of Down syndrome acute lymphoblastic leukemia

“… 8 First, we used short hairpin RNA (shRNA) interference to show that all five cell lines, disomic (N=2) or trisomic (N=3) and expressing either KRAS G12D or BCR-ABL oncogenes, were sensitive to Dyrk1a knock-down (KD) ( Figure 2A , B; Online Supplementary Figure S1I ). We next assessed the efficacy of new potent DYRK1A inhibitors using a DYRK1A-focused library which included EHT1610 used as control, Leucettinib-21 and its inactive isomer (compounds inspired by Leucettines and Leucettamine B, a natural substance produced by the marine sponge Leucetta microraphis ), 12 , 13 and three additional DYRK1A inhibitors whose chemical structure is based on the 7-azaindole scaffold, AM28, AM30 and AM45. 14 In dose-response experiments, we showed that AM30 and Leucettinib-21 were cytotoxic in both WT-KRAS G12D and Tc1-KRAS G12D cell lines ( Figure 2C ).…”