title: Identification of CXCR3 receptor agonists in combinatorial small-molecule libraries.
abstract: In a high-throughput screen of four million compounds from combinatorial libraries for small-molecule modulators of the chemokine receptor CXCR3, two classes of receptor agonists, based on tetrahydroisoquinoline and piperidinyl diazepanone templates, were identified. Several of these compounds stimulated calcium flux in HEK293 cells expressing the recombinant human CXCR3 receptor with efficacies and kinetics similar to those of native ligand CXCL11/I-TAC and stimulated chemotaxis of activated human T-cells. The agonist small molecules also inhibited binding of another CXCR3 ligand, CXCL10/IP-10, to the receptor. The response to small-molecule agonists was inhibited by a CXCR3-specific small-molecule antagonist previously identified within the same combinatorial compound collection but structurally unrelated to the agonists. Remarkably, while other, non-amino acid substituents were present in the majority of the library compounds screened, the agonists from both classes contained a positively charged amino acid component, with preference for Arg>Lys, as well as a hydrophobic component.
authors.affiliation: Pharmacopeia Drug Discovery, Inc., P.O. Box 5350, Princeton, NJ 08543, USA. ilana@pcop.com
authors.forename: Ilana L
authors.initials: IL
authors.lastname: Stroke
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Cole
authors.forename: Srilatha
authors.initials: S
authors.lastname: Simhadri
authors.forename: Marc-Raleigh
authors.initials: MR
authors.lastname: Brescia
authors.forename: Madhuri
authors.initials: M
authors.lastname: Desai
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Zhang
authors.forename: J Robert
authors.initials: JR
authors.lastname: Merritt
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Appell
authors.forename: Ian
authors.initials: I
authors.lastname: Henderson
authors.forename: Maria L
authors.initials: ML
authors.lastname: Webb
mesh_terms: D001671:Biochemistry / Q000379:methods; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000737:chemistry / Q000378:metabolism; D002633:Chemotaxis; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D011485:Protein Binding; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000819:agonists*; D013601:T-Lymphocytes / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; D008024:Ligands; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D044005:Tetrahydroisoquinolines