Chemokine receptors, CCR1, CCR2, CCR3 and CCR5 play an important role in cell adhesion, migration and inflammation. Hence they are drug targets for multiple sclerosis, asthma, atherosclerosis, cancer and other inflammatory diseases. There are dual and multiple target antagonists available for these receptors and it is not clear if they bind to similar sites in these chemokine receptors. We have applied the GPCRSimKit techniques to understand the structural basis of antagonist binding to these chemokine receptors [1-3]. The chemokine receptor CXCR4 is upregulated and has been implicated in 23 different human cancers. More importantly this receptor plays an important role in cell proliferation and metastasis of pancreatic cancer. Currently known antagonist for CXCR4 discovered originally for HIV viral entry, namely the cyclam compounds, are shown to increase cell proliferation in pancreatic cancer. So these compounds act as agonists in the pancreatic cancer cell lines. We have formed an interdisciplinary team at City of Hope to target CXCR4 and other chemokine receptors for pancreatic cancer. Dr. Joseph Kim and Dr. Richard Yip are collaborators in this project. Using an interdisciplinary approach combining computational predictions with in vitro screening, and in vivo experiments we have identified that chloroquine and its derivatives act as antagonists to CXCR4 in pancreatic cancer cell lines. We identified that chloroquine will be effective against human cancers that overexpress CXCR4. Based in this in silico, in vitro and in vivo study results, clinical trials are underway at City of Hope to test the efficacy of chloroquine alone and also in conjunction with chemotherapy for treating pancreatic cancer. Chloroquine has been shown to reduce pancreatic cancer in mouse models and also has shown efficacy in human clinical trials for glioblastoma. We have shown that this efficacy is conferred by chloroquine being an antagonist to CXCR4 receptor and in particular targeting the signaling pathway that leads to cell proliferation in pancreatic cancer cells.

Publications relevant to this project:

• Vaidehi, N., Schyler S., Trabanino R.J., Floriano, W.B., Abrol, R., Sharma S., Kochanny M., Koovakkat, S., Dunning L., Liang M., Fox J.M. de Mendoca F.L., Pease J., Goddard III, W.A and Horuk R., 2006, Predictions of CCR1 Chemokine Receptor Structure and BX 471 Antagonist Binding Followed By Experimental Validation, J. Biol. Chem. 281(37):27613-20.
• Hall S.E.,  Mao, A. Nicolaidou, V., Finelli, M., Wise, E.L., Nedjai, B., Kanjanapangka, J., Harirchian, P., Chen, D., Selchau, V., Ribeiro, S.,  Schyler, S., Pease, J.E.,  Horuk R., and Vaidehi, N. 2009, Elucidation of binding sites of dual antagonists in the human chemokine receptors CCR2 and CCR5. Mol. Pharm. 75, 1325-1336.
• Vaidehi, N., Pease, J. and Horuk R., 2009, Modeling Small Molecule Compound Binding to G-Protein Coupled Receptors, Methods in Enzymology, 460, 263-288.
• Lam AR, Bhattacharya S, Patel K, Hall SE, Mao A, Vaidehi N. 2011 Importance of receptor flexibility in binding of cyclam compounds to the chemokine receptor CXCR4 J Chem Inf Model. 24;51(1):139-47.