Discovery of potent LPA2 (EDG4) antagonists as potential anticancer agents.
The LPA(2) protein is overexpressed in many tumor cells. We report the optimization of a series of LPA(2) antagonists using calcium mobilization assay (aequorin assay) that led to the discovery of the first reported inhibitors selective for LPA(2). Key compounds were evaluated in vitro for inhibition of LPA(2) mediated Erk activation and proliferation of HCT-116 cells. These compounds could be used to evaluate the benefits of LPA(2) inhibition both in vitro and in vivo.
Beck
Hilary P
HP
Chemistry Research & Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. hbeck@amgen.com
Kohn
Todd
T
Rubenstein
Steven
S
Hedberg
Christine
C
Schwandner
Ralf
R
Hasslinger
Kerstin
K
Dai
Kang
K
Li
Cong
C
Liang
Lingming
L
Wesche
Holger
H
Frank
Brendon
B
An
Songhzu
S
Wickramasinghe
Dineli
D
Jaen
Juan
J
Medina
Julio
J
Hungate
Randall
R
Shen
Wang
W
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D049368:Receptors, Lysophosphatidic Acid; D048049:Extracellular Signal-Regulated MAP Kinases