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Targeting SDF-1/CXCL12 with a ligand that prevents activation of CXCR4 through structure-based drug design. J Am Chem Soc 2010 Jun 02;132(21):7242-3 PMID: 20459090 PMCID: PMC2941798


CXCL12 is an attractive target for clinical therapy because of its involvement in autoimmune diseases, cancer growth, metastasis, and neovascularization. Tyrosine sulfation at three positions in the CXCR4 N-terminus is crucial for specific, high-affinity CXCL12 binding. An NMR structure of the complex between the CXCL12 dimer and a sulfotyrosine-containing CXCR4 fragment enabled high-throughput in silico screening for inhibitors of the chemokine-receptor interface. A total of 1.4 million compounds from the ZINC database were docked into a cleft on the CXCL12 surface normally occupied by sulfotyrosine 21 (sY21), and five were selected for experimental screening. NMR titrations with CXCL12 revealed that four of the compounds occupy the sY21 site, one of which binds with a K(d) of 64 microM. This compound selectively inhibits SDF1-induced CXCR4 signaling in THP1 cells. Our results suggest that sulfotyrosine recognition sites can be targeted for the development of novel chemokine inhibitors.

Author List

Veldkamp CT, Ziarek JJ, Peterson FC, Chen Y, Volkman BF


Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Chemokine CXCL12
Computer Simulation
Drug Design
Drug Screening Assays, Antitumor
Models, Chemical
Receptors, CXCR4
Small Molecule Libraries
Structure-Activity Relationship

View this publication's entry at the Pubmed website PMID: 20459090
jenkins-FCD Prod-185 20a1a87aaef305b3f5a3e8bb55f731baa68cadd0