Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors

Hongbo Zeng; David B Belanger; Patrick J Curran; Gerald W Shipps Jr; Hua Miao; Jack B Bracken; M Arshad Siddiqui; Michael Malkowski; Yan Wang

doi:10.1016/j.bmcl.2011.07.101

Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5870-5. doi: 10.1016/j.bmcl.2011.07.101. Epub 2011 Aug 3.

Authors

Hongbo Zeng¹, David B Belanger, Patrick J Curran, Gerald W Shipps Jr, Hua Miao, Jack B Bracken, M Arshad Siddiqui, Michael Malkowski, Yan Wang

Affiliation

¹ Department of Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, United States. [email protected]

PMID: 21855335
DOI: 10.1016/j.bmcl.2011.07.101

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.

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Animals
Aurora Kinases
Breast Neoplasms / drug therapy
Breast Neoplasms / enzymology*
Breast Neoplasms / genetics
Computer Simulation
DNA-Binding Proteins / metabolism
Dasatinib
Dose-Response Relationship, Drug
Drug Design
Drug Discovery
Drug Screening Assays, Antitumor
Female
Humans
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacokinetics
Imidazoles / pharmacology*
Inhibitory Concentration 50
Melanocytes / physiology
Mice
Molecular Targeted Therapy
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / genetics
Oncogenes
Phenotype
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / genetics
Proto-Oncogenes
Pyrazines / chemical synthesis*
Pyrazines / chemistry
Pyrazines / pharmacokinetics
Pyrazines / pharmacology*
Pyrimidines / metabolism
RNA-Binding Proteins / metabolism
Structure-Activity Relationship
Thiazoles / metabolism

Substances

Adaptor Proteins, Signal Transducing
DNA-Binding Proteins
Imidazoles
KHDRBS1 protein, human
Neoplasm Proteins
Protein Kinase Inhibitors
Pyrazines
Pyrimidines
RNA-Binding Proteins
Thiazoles
Protein-Tyrosine Kinases
PTK6 protein, human
Aurora Kinases
Protein Serine-Threonine Kinases
Dasatinib