ARRY 520 trifluoroacetate

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].

References:[1] Woessner R, Tunquist B, Lemieux C, Chlipala E, Jackinsky S, Dewolf W Jr, Voegtli W, Cox A, Rana S, Lee P, Walker D. ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models. Anticancer Res. 2009;29(11):4373-80.[2] Khoury HJ, Garcia-Manero G, Borthakur G, Kadia T, Foudray MC, Arellano M, Langston A, Bethelmie-Bryan B, Rush S, Litwiler K, Karan S, Simmons H, Marcus AI, Ptaszynski M, Kantarjian H. A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias. Cancer. 2012;118(14):3556-64.

Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520.[Pubmed:20571074]

Mol Cancer Ther. 2010 Jul;9(7):2046-56.

Kinesin spindle protein (KSP/Eg5) inhibitors are novel anticancer agents that have thus far shown only modest activity in the clinic. Understanding how to identify patients who may be most sensitive to treatment is clearly needed to improve the development of these molecules. We studied four multiple myeloma cell lines treated with the KSP inhibitor ARRY-520 to identify factors important for initiating apoptosis while cells are arrested in mitosis. The majority (three of four) of cell lines underwent mitotic arrest, with apoptosis occurring in mitosis within 24 to 30 hours. The remaining line (NCI H929) is temporally refractory to ARRY-520 treatment, undergoing mitotic slippage and subsequently peaking in apoptotic markers after 72 hours of treatment, while most cells are in interphase. Interestingly, loss of the antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) coincided with mitotic cell death. Stabilization of Mcl-1 resulted in a delayed onset of apoptosis, whereas enforced downregulation of Mcl-1 increased cell death in response to KSP inhibition. Thus, variation in responses to KSP inhibition is governed by a balance between survival proteins and spindle checkpoint integrity. Cells relying on short-lived survival proteins during mitosis are more likely to undergo apoptosis in response to KSP inhibition. We propose that patients with hematologic malignancies, which rely on Mcl-1, would therefore be good candidates for treatment with KSP inhibitors.

KSP inhibitor ARRY-520 as a substitute for Paclitaxel in Type I ovarian cancer cells.[Pubmed:19619321]

J Transl Med. 2009 Jul 20;7:63.

BACKGROUND: We previously described a sub-population of epithelial ovarian cancer (EOC) cells with a functional TLR-4/MyD88/NF-kappaB pathway (Type I EOC cells), which confers the capacity to respond to Paclitaxel, a known TLR-4 ligand, by enhancing NF-kappaB activity and upregulating cytokine secretion - events that are known to promote tumor progression. It is therefore important to distinguish those patients that should not receive Paclitaxel; it is also important to identify alternative chemotherapy options that would benefit this sub-group of patients. The objective of this study is to determine if the KSP inhibitor, ARRY-520, can be a substitute for Paclitaxel in patients with Type I EOC. METHODS: EOC cells isolated from either ascites or tumor tissue were treated with increasing concentrations of ARRY-520 or Paclitaxel and cell viability determined. Activation of the apoptotic pathway was determined using Western blot analysis. Mitochondrial integrity was quantified using JC1 dye. Cytokine profiling was performed from supernatants using xMAP technology. NF-kappaB activity was measured using a Luciferase reporter system. In vivo activity was determined using a subcutaneous xenograft mouse model. RESULTS: ARRY-520 and Paclitaxel exhibited the same cytotoxic effect on Type I and II cells. The GI50 at 48 h for Type II EOC cells was 0.0015 microM and 0.2 microM for ARRY-520 and Paclitaxel, respectively. For Type I EOC cells, the GI50 at 48 h was > 3 microM and >20 microM for ARRY-520 and Paclitaxel, respectively. Decrease in the number of viable cells was accompanied by mitochondrial depolarization and caspase activation. Unlike Paclitaxel, ARRY-520 did not induce NF-kappaB activation, did not enhance cytokine secretion, nor induce ERK phosphorylation in Type I EOC cells. CONCLUSION: Administration of Paclitaxel to patients with high percentage Type I cancer cells could have detrimental effects due to Paclitaxel-induced enhancement of NF-kappaB and ERK activities, and cytokine production (e.g. IL-6), which promote chemoresistance and tumor progression. ARRY-520 has similar anti-tumor activity in EOC cells as that of Paclitaxel. However, unlike Paclitaxel, it does not induce these pro-tumor effects in Type I cells. Therefore, the KSP inhibitor ARRY-520 may represent an alternative to Paclitaxel in this subgroup of EOC patients.

ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models.[Pubmed:20032381]

Anticancer Res. 2009 Nov;29(11):4373-80.

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 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.

Potent and selective kinesin spindle protein (KSP) inhibitor; induces Mcl-1 degradation,ARRY-520 is a synthetic kinesin spindle protein (KSP) inhibitor with IC₅₀ of 6 nM.

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