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ARRY 520 trifluoroacetate is a synthetic and salt form of KSP inhibitor with IC50 value of 6 nM.

Kinesin spindle protein (KSP) is one member of the mitotic kinesins involved in the early stages of mitosis responsible for centrosome separation.

In vitro: ARRY-520 had low nanomolar antiproliferative activity in various tumor cell lines and exhibited activity in multidrug-resistant cell lines. EC50s of ARRY-520 for proliferation inhibition in HCT-15, NCI/ADR-RES and K562/ADR cells was 3.7, 14 and 4.2 nM, respectively, while paclitaxel EC50s in these cell lines was 35, 565 and 372 nM. Moreover, K562/ADR was found to be 118-fold resistant to paclitaxel when compared to the parent K562 line, but only 3.5-fold resistant to that of ARRY-520 [1].

In vivo: ARRY-520 was found to be active in UISO-BCA-1 xenografts, which were completely resistant to paclitaxel. The antitumor efficacy of ARRY-520 was also found to be superior to paclitaxel in mice bearing HT-29, HCT-116, MDA-MB-231 and A2780 xenografts. ARRY-520 was superior to docetaxel in the androgen receptor-negative prostate cancer PC-3 xenograft model, and was also superior to docetaxel in the DU145 prostate xenograft model [1].

Clinical trial: A phase I trial was conducted to establish the safety and the maximum tolerated dose (MTD) of ARRY-520. The MTD was 4.5 mg/m2 total dose per cycle for both dose schedules. Dose-limiting toxicities included exfoliative rash, hand-foot-syndrome, mucositis, and hyperbilirubinemia. Grades 3 or 4 reversible drug-related myelosuppression were observed in 33 of 36 patients [2].

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