ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models.

Aim: Profiling the efficacy and pharmaco- dynamic activity of the kinesin spindle protein (KSP) inhibitor ARRY-520 will aid the identification of responsive tumor types and pharmacodynamic profiles that correlate with activity. Materials and Methods: In vivo activity was evaluated in a diverse panel of 16 different tumor xenograft models. Pharmacodynamic activity was evaluated in selected models. Results: ARRY-520 had low nanomolar antiproliferative activity in tumor cell lines. Monopolar spindles were formed at active potencies. Partial or complete responses were observed in 13/16 xenograft models. Hematological tumors were particularly sensitive, with a 100% complete response rate in some models. Maintenance of mitotic block for a sufficient length of time for cells to lose survival signals and progress to apoptosis was a key component of the mechanism of activity. ARRY- 520 was also active in several taxane resistant models. Conclusion: The data provide a rationale for clinical evaluation of the activity of ARRY-520 in hematological carcinomas and taxane-resistant tumors. Anti-mitotic therapy has proven clinical benefit in the treatment of cancer. Taxanes and epothilones, which stabilize microtubule polymers, and vinca alkaloids, which inhibit tubulin polymerization, are used to treat a variety of carcinomas, including breast, ovarian, lung and leukemias