Modulation of cofilin phosphorylation by inhibition of the Lim family kinases.
A series of aminothiazoles that are potent inhibitors of LIM kinases 1 and 2 is described. Appropriate choice of substituents led to molecules with good selectivity for either enzyme. An advanced member of the series was shown to effectively interfere with the phosphorylation of the LIM kinases substrate cofilin. Consistent with the important role of the LIM kinases in regulating cytoskeletal structure, treated cells displayed dramatically reduced F-actin content.
Oncology Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, USA. liqi.he@bms.com
Liqi
L
He
Steven P
SP
Seitz
George L
GL
Trainor
David
D
Tortolani
Wayne
W
Vaccaro
Michael
M
Poss
Christine M
CM
Tarby
John S
JS
Tokarski
Becky
B
Penhallow
Chen-Yi
CY
Hung
Ricardo
R
Attar
Tai-An
TA
Lin
D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D002460:Cell Line; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D051339:Actin Depolymerizing Factors; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C515892:LIMK1 protein, human; C102895:LIMK2 protein, human; D054461:Lim Kinases