title: Discovery of potent small molecule inhibitors of DYRK1A by structure-based virtual screening and bioassay.
abstract: In this study, six novel dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) inhibitors with IC(50) values ranging from 1.51 to 88.13 μM were successfully identified through virtual screening and in vitro plus cell based bioassay. Compound 5 with IC(50) value of 1.51 μM is the most potent hit against DYRK1A in vitro, while compound 3 exhibited the most potent activity in cultured cells. The inhibition mechanism was explored by molecular docking approach. This study may provide a start point for further mechanism based study as well as discovery of drug candidate against Down syndrome (DS).
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Yexiong
authors.initials: Y
authors.lastname: Tan
authors.forename: Liwei
authors.initials: L
authors.lastname: Dong
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001671:Biochemistry / Q000379:methods; D001681:Biological Assay / Q000379:methods*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004314:Down Syndrome / Q000188:drug therapy*; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D051379:Mice; D008822:Mice, Transgenic; D008956:Models, Chemical; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000097603:Dyrk Kinases
chemical_list: D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases