Pharmacological characterization of INCB3344, a small molecule antagonist of human CCR2.
The chemokine receptor 2 (CCR2) directs migration of monocytes and has been proposed to be a drug target for chronic inflammatory diseases. INCB3344 was first published as a small molecule nanomolar inhibitor of rodent CCR2. Here, we show that INCB3344 can also bind human CCR2 (hCCR2) with high affinity, having a dissociation constant (K(d)) of approximately 5nM. The binding of the compound to the receptor is rapid and reversible. INCB3344 potently inhibits hCCR2 binding of monocyte chemoattractant protein-1 (MCP-1) and MCP-1-induced signaling and function in hCCR2-expressing cells, including ERK phosphorylation and chemotaxis, and is competitive against MCP-1 in vitro. INCB3344 also blocks MCP-1 binding to monocytes in human whole blood, with potency consistent with in vitro studies. The whole blood binding assay described here can be used for monitoring pharmacodynamic activity of CCR2 antagonists in both preclinical models and in the clinic.
Shin
Niu
N
Department of In Vitro Biology, Incyte Corporation, Wilmington, DE, United States.
Baribaud
Frédéric
F
Wang
Kathy
K
Yang
Genjie
G
Wynn
Rich
R
Covington
Maryanne B
MB
Feldman
Patricia
P
Gallagher
Karen B
KB
Leffet
Lynn M
LM
Lo
Yvonne Y
YY
Wang
Anlai
A
Xue
Chu-Biao
CB
Newton
Robert C
RC
Scherle
Peggy A
PA
D001681:Biological Assay; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D002633:Chemotaxis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*
C515334:CCR2 protein, human; D018932:Chemokine CCL2; C505875:INCB3344; D011759:Pyrrolidines; D054390:Receptors, CCR2; D048049:Extracellular Signal-Regulated MAP Kinases