ARRY-520, a Novel KSP Inhibitor with Potent Activity in Hematological and Taxane-resistant Tumor Models

作者：Woessner Richard^*; Tunquist Brian; Lemieux Christine; Chlipala Elizabeth; Jackinsky Steve; Dewolf Walter Jr; Voegtli Walter; Cox April; Rana Sumeet; Lee Patrice; Walker Duncan

来源：Anticancer Research, 2009, 29(11): 4373-4380.

• ARRY-520
• KSP inhibitor
• hematological tumors
• taxane resistant

Aim: Profiling the efficacy, and pharmacodynamic 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 13116 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.

• 出版日期2009-11