1 We investigated the e ects of a number of naturally occurring chemokines (MIP-1a, MIP-1b, RANTES, MCP-2, MCP-3, MCP-4) on di erent processes linked to the chemokine receptor CCR5 in recombinant CHO cells expressing the receptor at di erent levels. 2 Internalization of CCR5 following chemokine treatment was studied and MIP-1a, MIP-1b and RANTES (50 nM) were able to induce internalization (*50%) of the receptor. Internalization due to MCP-2, MCP-3 and MCP-4 was less (*20%). 3 Phosphorylation of CCR5 following chemokine treatment was studied and MIP-1a, MIP-1b and RANTES (50 nM) were able to induce phosphorylation of CCR5 whereas the other chemokines did not induce CCR5 phosphorylation. 4 MIP-1a, MIP-1b, RANTES and MCP-2 were able to stimulate [ 35 S]-GTPgS binding, an index of receptor/G protein activation, whereas MCP-3 and MCP-4 had no e ect in this assay. MCP-2 was a partial agonist (*80%) compared to MIP-1a, MIP-1b and RANTES, which gave similar maximal stimulations in this assay. 5 MIP-1a, MIP-1b, RANTES, MCP-2 and MCP-4 were able to stimulate increases in intracellular calcium ions via activation of CCR5 whereas MCP-3 was without e ect. 6 It is concluded that di erent chemokines interacting with CCR5 mediate di erent patterns of cellular responses.

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S100P, a calcium-binding protein, is known to advance tumor progression and metastasis in pancreatic and several other cancers. Herein is described the in silico identification of a putative binding pocket of S100P to identify, synthesize and evaluate novel small molecules with the potential to selectively bind S100P and inhibit its activation of cell survival and metastatic pathways. The virtual screening of a drug-like database against the S100P model led to the identification of over 100 clusters of diverse scaffolds. A representative test set identified a number of structurally unrelated hits that inhibit S100P-RAGE interaction, measured by ELISA, and reduce in vitro cell invasion selectively in S100P-expressing pancreatic cancer cells at 10 μM. This study establishes a proof of concept in the potential for rational design of small molecule S100P inhibitors for drug candidate development.