MCP110

MCP compounds were developed with the idea to inhibit RAS/RAF interaction. They were identified by carrying out high-throughput screens of chemical compounds for their ability to inhibit RAS/RAF interaction in the yeast two-hybrid assay. A number of compounds including MCP1, MCP53, and MCP110 were identified as active compounds. Their inhibition of the RAS signaling was demonstrated by examining RAF and MEK activities, phosphorylation of ERK as well as characterizing their effects on events downstream of RAF. Direct evidence for the inhibition of RAS/RAF interaction was obtained by carrying out co-IP experiments. MCP compounds inhibit proliferation of a wide range of human cancer cell lines. Combination studies with other drugs showed that MCP compounds synergize with MAPK pathway inhibitors as well as with microtubule-targeting chemotherapeutics. In particular, a strong synergy with paclitaxel was observed. Efficacy to inhibit tumor formation was demonstrated using mouse xenograft models. Combination of MCP110 and paclitaxel was particularly effective in inhibiting tumor growth in a mouse xenograft model of colorectal carcinoma.

An important clinical task is to coherently integrate the use of protein-targeted drugs into preexisting therapeutic regimens, with the goal of improving treatment efficacy. Constitutive activation of Ras-dependent signaling is important in many tumors, and agents that inhibit this pathway might be useful in numerous therapeutic combinations. The MCP compounds were identified as inhibitors of Ras-Raf interactions and previously shown to inhibit multiple Ras-dependent transformation phenotypes when used as monoagents in cell culture analyses. In this study, we investigate the ability of the MCP110 compound to synergistically enhance the activity of other therapeutic agents. In both a defined K-Ras–transformed fibroblast model and in human tumor cell lines with mutationally activated Ras, MCP110 selectively synergizes with other agents targeting the mitogen-activated protein kinase pathway, and with multiple agents (paclitaxel, docetaxel, and vincristine) targeting the microtubule network. The synergistic activity of MCP110 and paclitaxel was further established by experiments showing that in Kaposi's sarcoma oncogenically transformed cell lines, cellular models for tumors treated with taxanes in the clinic and in which Raf-dependent signaling plays an important role, MCP110 synergizes with paclitaxel and limit growth. Finally, in vivo testing indicate that MCP110 is bioavailable, inhibits the growth of LXFA 629 lung and SW620 colon carcinoma cells in xenograft models, and again strongly synergizes with paclitaxel. Together, these findings indicate that MCP compounds have potential to be effective in combination with other anticancer agents. [Mol Cancer Ther 2007;6(3):898–906]