Potent and selective mitogen-activated protein kinase kinase (MEK) 1,2 inhibitors. 1. 4-(4-bromo-2-fluorophenylamino)-1- methylpyridin-2(1H)-ones.
The role of MEK 1,2 in cancer tumorgenesis has been clearly demonstrated preclinically, and two selective inhibitors are currently undergoing clinical evaluation to determine their role in the human disease. We have discovered 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones as a new class of ATP noncompetitive MEK inhibitors. These inhibitors exhibit excellent cellular potency and good pharmacokinetic properties and have demonstrated the ability to inhibit ERK phosphorylation in HT-29 tumors from mouse xenograft studies.
Wallace
Eli M
EM
Array BioPharma, Boulder, Colorado 80301, USA. ewallace@arraybiopharma.com
Lyssikatos
Joseph
J
Blake
James F
JF
Seo
Jeongbeob
J
Yang
Hong Woon
HW
Yeh
Tammie C
TC
Perrier
Michele
M
Jarski
Heidi
H
Marsh
Vivienne
V
Poch
Gregory
G
Livingston
Michelle Goyette
MG
Otten
Jennifer
J
Hingorani
Gary
G
Woessner
Rich
R
Lee
Patrice
P
Winkler
James
J
Koch
Kevin
K
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D004355:Drug Stability; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D010766:Phosphorylation; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011725:Pyridines; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2