title: Ensemble docking-based virtual screening yields novel spirocyclic JAK1 inhibitors.
abstract: Small molecule inhibition of Janus kinases (JAKs) has been demonstrated as a viable strategy for the treatment of various inflammatory conditions and continues to emerge in cancer-related indications. In this study, a large supplier database was screened to identify novel chemistry starting points for JAK1. The docking-based screening was followed up by testing ten hit compounds experimentally, out of which five have displayed single-digit micromolar and submicromolar IC50values on JAK1. Thus, the study was concluded with the discovery of five novel JAK inhibitors from a tiny screening deck with a remarkable hitrate of 50%. The results have highlighted spirocyclic pyrrolopyrimidines with submicromolar JAK1 IC50values and a preference for JAK1 over JAK2 as potential starting points in developing a novel class of JAK1 inhibitors.
authors: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2., Budapest 1117, Hungary.
authors: Dávid
authors: D
authors: Bajusz
authors: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2., Budapest 1117, Hungary.
authors: György G
authors: GG
authors: Ferenczy
authors: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2., Budapest 1117, Hungary. Electronic address: keseru.gyorgy@ttk.mta.hu.
authors: György M
authors: GM
authors: Keserű
mesh_terms: D019540:Area Under Curve; D004353:Drug Evaluation, Preclinical; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008024:Ligands; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D012372:ROC Curve; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D013141:Spiro Compounds; D053613:Janus Kinase 1
keywords: Ensemble docking; JAK1; Janus kinase; Kinase inhibitor; Spirocyclic compounds; Virtual screening