Structure-based drug design of a highly potent CDK1,2,4,6 inhibitor with novel macrocyclic quinoxalin-2-one structure

Nobuhiko Kawanishi; Tetsuya Sugimoto; Jun Shibata; Kaori Nakamura; Kouta Masutani; Mari Ikuta; Hiroshi Hirai

doi:10.1016/j.bmcl.2006.07.026

Structure-based drug design of a highly potent CDK1,2,4,6 inhibitor with novel macrocyclic quinoxalin-2-one structure

Bioorg Med Chem Lett. 2006 Oct 1;16(19):5122-6. doi: 10.1016/j.bmcl.2006.07.026. Epub 2006 Jul 28.

Authors

Nobuhiko Kawanishi¹, Tetsuya Sugimoto, Jun Shibata, Kaori Nakamura, Kouta Masutani, Mari Ikuta, Hiroshi Hirai

Affiliation

¹ Department of Medicinal Chemistry, Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan. [email protected]

PMID: 16876403
DOI: 10.1016/j.bmcl.2006.07.026

Abstract

The design of a novel series of cyclin-dependent kinase (CDK) inhibitors containing a macrocyclic quinoxaline-2-one is reported. Structure-based drug design and optimization from the starting point of diarylurea 2, which we previously reported as a moderate CDK1,2,4,6 inhibitor [J. Biol.Chem.2001, 276, 27548], led to the discovery of potent CDK1,2,4,6 inhibitor that were suitable for iv administration for in vivo study.

MeSH terms

Animals
Binding Sites
CDC2 Protein Kinase / antagonists & inhibitors
CDC2-CDC28 Kinases / antagonists & inhibitors*
Crystallography, X-Ray
Cyclin-Dependent Kinase 2 / antagonists & inhibitors
Cyclin-Dependent Kinase 4 / antagonists & inhibitors
Cyclin-Dependent Kinase 6 / antagonists & inhibitors
Drug Design
Humans
Hydrogen Bonding
Inhibitory Concentration 50
Macrocyclic Compounds / chemical synthesis
Macrocyclic Compounds / pharmacology
Molecular Structure
Quinoxalines / chemical synthesis*
Quinoxalines / pharmacology*
Structure-Activity Relationship

Substances

Macrocyclic Compounds
Quinoxalines
CDC2 Protein Kinase
CDC2-CDC28 Kinases
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6