title: Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors.
abstract: A series of substituted imidazo[1,2-a]pyrazin-8-amines were discovered as novel breast tumor kinase (Brk)/protein tyrosine kinase 6 (PTK6) inhibitors. Tool compounds with low-nanomolar Brk inhibition activity, high selectivity towards other kinases and desirable DMPK properties were achieved to enable the exploration of Brk as an oncology target.
authors.affiliation: Department of Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, United States. zenghb@hotmail.com
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zeng
authors.forename: David B
authors.initials: DB
authors.lastname: Belanger
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Curran
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Shipps
authors.forename: Hua
authors.initials: H
authors.lastname: Miao
authors.forename: Jack B
authors.initials: JB
authors.lastname: Bracken
authors.forename: M
authors.initials: M
authors.lastname: Arshad Siddiqui
authors.forename: Michael
authors.initials: M
authors.lastname: Malkowski
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D064127:Aurora Kinases; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000378:metabolism; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008544:Melanocytes / Q000502:physiology; D051379:Mice; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009857:Oncogenes; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011519:Proto-Oncogenes; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D007093:Imidazoles; C489559:KHDRBS1 protein, human; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D016601:RNA-Binding Proteins; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D000069439:Dasatinib