MKC-1 (previously Ro31-7453) is a novel, orally active cell cycle inhibitor with in vitro and in vivo activity against a wide range of human solid tumor cell lines, including multi-drug resistant cell lines. MKC-1 has been tested in over 270 solid tumor patients to date and is currently in Phase II clinical trials for solid tumors and Phase I clinical trials for leukemia patients. The strong pre-clinical activity of MKC-1 towards solid tumor lines and signs of efficacy in the initial clinical evaluation with lack of neuropathy and cardiotoxicity suggests that MKC-1 may also be of clinical benefit in the treatment of hematopoietic cancers. The antiproliferative activity of MKC-1 was examined against a panel of hematopoietic cell lines including HL-60, U937, MV4;11, THP-1, Jurkat, and OCI-AML 1-5. MKC-1 showed potent and dose-dependent activity towards these cell lines, with IC50 values in the range of 20 - 400 nM. MKC-1 also inhibited in vitro growth of primary cells derived from AML and CML patients. Additionally, MKC-1 showed enhanced activity with Ara-C in combination studies in vitro when added either simultaneously or sequentially using the cell line OCI-AML 4. Binding studies have shown that MKC-1 binds to the colchicine binding site of tubulin and to members of the importin beta family of proteins. Consistent with these results, cell cycle arrest in the G2/M phase of the cell cycle followed by apoptosis was observed in cell lines and patient samples treated with MKC-1. Immunofluorescence analysis of cells treated with MKC-1 revealed that the drug induced a disruption of the microtubule network and the formation of aberrant mitotic spindles. Furthermore, MKC-1 was also shown to induce a dose-dependent reduction in the levels of both phospho-Akt and phospho-p70S6K kinases through Western blot analysis of treated THP-1 cells. In conclusion, our results indicate MKC-1 arrests the cell cycle and disrupts multiple survival pathways to induce apoptosis in hematopoietic cell lines and patient samples. These results suggest that MKC-1 may have clinical potential in the treatment of leukemia either alone or in combination with other agents.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA