CXCR3 is not targeted by compounds in the Millenium pipeline, i.e., this appears to be a new approach for them. Presumably I-TAC (4-73) is the compound they are starting with, but the patent application mentions antibodies. More from the same team:
>>J. Biol. Chem., Vol. 278, Issue 1, 289-295, January 3, 2003
Structure-Function Relationship between the Human Chemokine Receptor CXCR3 and Its Ligands*
Ian Clark-Lewis§, Ivan Mattioli¶, Jiang-Hong Gong, and Pius Loetscher¶§
From the Biomedical Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada and the ¶ Theodor-Kocher Institute, University of Bern, CH-3000 Bern 9, Switzerland
Received for publication, September 16, 2002, and in revised form, October 30, 2002
I-TAC, IP10, and Mig are interferon- inducible CXC chemokines that share the same G-protein-coupled receptor CXCR3, which is preferentially expressed on Th1 lymphocytes. We have explored the structure-function relationship of the CXCR3 ligands, in particular of I-TAC, which has highest affinity for CXCR3 and is the most potent agonist. A potent antagonist for CXCR3 was obtained by NH2-terminal truncation of I-TAC. I-TAC (4-73), which lacks the first three residues, has no agonistic activity but competes for the binding of I-TAC to CXCR3-bearing cells and inhibits migration and Ca2+ changes in such cells in response to stimulation with I-TAC, IP10, and Mig. It does also not induce internalization of CXCR3, which is in support of the lack of agonistic effects. Hybrid chemokines between I-TAC and IP10 were used to identify regions responsible for the higher activity of I-TAC. I-TAC-like IP10 analogs are obtained by substituting the NH2 terminus (residues 1-8) or N-loop region (residues 12-17) of IP10 with those of I-TAC, suggesting that the differences in function of the CXCR3 ligands can be assigned to distinct regions and that these regions are interchangeable. Structure-activity studies with Mig showed that the extended basic COOH-terminal region, which is not present in I-TAC and IP10, is important for binding and activity.<<
jbc.org
Also a freebie.
Cheers, Tuck |
