Synthesis and structure-activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors

Andreas Reichelt; Julie M Bailis; Michael D Bartberger; Guomin Yao; Hong Shu; Matthew R Kaller; John G Allen; Margaret F Weidner; Kathleen S Keegan; Jennifer H Dao

doi:10.1016/j.ejmech.2014.04.013

Synthesis and structure-activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors

Eur J Med Chem. 2014 Jun 10:80:364-82. doi: 10.1016/j.ejmech.2014.04.013. Epub 2014 Apr 5.

Authors

Affiliations

¹ Medicinal Chemistry, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: [email protected].
² Oncology Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
³ Molecular Structure and Characterization, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
⁴ Medicinal Chemistry, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.

PMID: 24793884
DOI: 10.1016/j.ejmech.2014.04.013

Abstract

The Cell division cycle 7 (Cdc7) protein kinase is essential for DNA replication and maintenance of genome stability. We systematically explored thiazole-based compounds as inhibitors of Cdc7 kinase activity in cancer cells. Our studies resulted in the identification of a potent, selective Cdc7 inhibitor that decreased phosphorylation of the direct substrate MCM2 in vitro and in vivo, and inhibited DNA synthesis and cell viability in vitro.

Keywords: Cdc7; DNA replication; Kinase inhibitor; MCM2; Thiazole.

MeSH terms

Animals
Catalytic Domain
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Chemistry Techniques, Synthetic
Female
HCT116 Cells
Humans
Inhibitory Concentration 50
Male
Mice
Minichromosome Maintenance Complex Component 2 / metabolism
Molecular Docking Simulation
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / metabolism
Rats
Structure-Activity Relationship
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / metabolism
Thiazoles / pharmacology*
Xenograft Model Antitumor Assays

Substances

Cell Cycle Proteins
Protein Kinase Inhibitors
Thiazoles
CDC7 protein, human
Protein Serine-Threonine Kinases
MCM2 protein, human
Minichromosome Maintenance Complex Component 2