Design and synthesis of 2-amino-isoxazolopyridines as Polo-like kinase inhibitors

Emily J Hanan; Raymond V Fucini; Michael J Romanowski; Robert A Elling; Willard Lew; Hans E Purkey; Erica C VanderPorten; Wenjin Yang

doi:10.1016/j.bmcl.2008.08.091

Design and synthesis of 2-amino-isoxazolopyridines as Polo-like kinase inhibitors

Bioorg Med Chem Lett. 2008 Oct 1;18(19):5186-9. doi: 10.1016/j.bmcl.2008.08.091. Epub 2008 Aug 29.

Authors

Emily J Hanan¹, Raymond V Fucini, Michael J Romanowski, Robert A Elling, Willard Lew, Hans E Purkey, Erica C VanderPorten, Wenjin Yang

Affiliation

¹ Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard Suite 400, South San Francisco, CA 94080, USA. [email protected]

PMID: 18790636
DOI: 10.1016/j.bmcl.2008.08.091

Abstract

A series of 2-amino-isoxazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors. Key SAR and crystallographic data are discussed. More advanced analogues inhibit Plk1 with good enzymatic activity and modest cell-based activity. Differential selectivity among the three Plk isoforms is observed.

MeSH terms

Cell Cycle Proteins / antagonists & inhibitors*
Combinatorial Chemistry Techniques
Crystallography, X-Ray
Drug Design*
Drug Screening Assays, Antitumor
Humans
Isoenzymes / antagonists & inhibitors
Isoxazoles / chemical synthesis*
Isoxazoles / chemistry
Isoxazoles / pharmacology*
Microsomes, Liver / drug effects
Molecular Conformation
Molecular Structure
Polo-Like Kinase 1
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins / antagonists & inhibitors*
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Cell Cycle Proteins
Isoenzymes
Isoxazoles
Proto-Oncogene Proteins
Pyridines
Protein Serine-Threonine Kinases