Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding

Kyle A Emmitte; George M Adjabeng; C Webb Andrews; Jennifer G Badiang Alberti; Ramesh Bambal; Stanley D Chamberlain; Ronda G Davis-Ward; Hamilton D Dickson; Daniel F Hassler; Keith R Hornberger; Jeffrey R Jackson; Kevin W Kuntz; Timothy J Lansing; Robert A Mook Jr; Kristen E Nailor; Mark A Pobanz; Stephon C Smith; Chiu-Mei Sung; Mui Cheung

doi:10.1016/j.bmcl.2009.01.094

Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1694-7. doi: 10.1016/j.bmcl.2009.01.094. Epub 2009 Jan 31.

Affiliation

¹ Five Moore Drive, Research Triangle Park, NC 27709, GlaxoSmithKline, USA.

PMID: 19237286
DOI: 10.1016/j.bmcl.2009.01.094

Abstract

A series of thiophene PLK1 inhibitors was optimized for increased solubility and reduced protein binding through the appendage of basic amine functionality. Interesting selectivity between PLK1 and PLK3 was also obtained through these modifications.

MeSH terms

Cell Cycle
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry
Cell Line, Tumor
Chemistry, Pharmaceutical / methods*
Drug Design
Humans
Inhibitory Concentration 50
Mitosis
Models, Chemical
Molecular Conformation
Polo-Like Kinase 1
Protein Binding
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / chemistry
Solubility
Thiophenes / chemistry*
Tumor Suppressor Proteins

Substances

Cell Cycle Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Thiophenes
Tumor Suppressor Proteins
PLK3 protein, human
Protein Serine-Threonine Kinases