Identification of novel, potent and selective inhibitors of Polo-like kinase 1

Shaoqing Chen; David Bartkovitz; Jianping Cai; Yi Chen; Zhi Chen; Xin-Jie Chu; Kang Le; Nam T Le; Kin-Chun Luk; Steve Mischke; Goli Naderi-Oboodi; John F Boylan; Tom Nevins; Weiguo Qing; Yingsi Chen; Peter M Wovkulich

doi:10.1016/j.bmcl.2011.11.052

Identification of novel, potent and selective inhibitors of Polo-like kinase 1

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1247-50. doi: 10.1016/j.bmcl.2011.11.052. Epub 2011 Dec 1.

Authors

Shaoqing Chen¹, David Bartkovitz, Jianping Cai, Yi Chen, Zhi Chen, Xin-Jie Chu, Kang Le, Nam T Le, Kin-Chun Luk, Steve Mischke, Goli Naderi-Oboodi, John F Boylan, Tom Nevins, Weiguo Qing, Yingsi Chen, Peter M Wovkulich

Affiliation

¹ Discovery Chemistry, Hoffmann-La Roche Inc., Pharma Research & Early Development, Small Molecule Research, 340 Kingsland Street, Nutley, NJ 07110, United States. shaoqing.chen@roche.com

PMID: 22172702
DOI: 10.1016/j.bmcl.2011.11.052

Abstract

A series of pyrimidodiazepines was identified as potent Polo-like kinase 1 (PLK1) inhibitors. The synthesis and SAR are discussed. The lead compound 7 (RO3280) has potent inhibitory activity against PLK1, good selectivity against other kinases, and excellent in vitro cellular potency. It showed strong antitumor activity in xenograft mouse models.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Azepines / chemical synthesis
Azepines / chemistry
Azepines / pharmacology*
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Humans
Mice
Molecular Structure
Neoplasms, Experimental / drug therapy*
Polo-Like Kinase 1
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Stereoisomerism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Azepines
Cell Cycle Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidines
RO3280
Protein Serine-Threonine Kinases