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ATM-3507

產品活性：ATM-3507 是原肌球蛋白 (tropomyosin) 的一個有效抑制劑，其在人類黑色素瘤細胞系中的 IC₅₀ 值約為 3.83-6.84 μM。

研究領域：Cytoskeleton

作用靶點：Myosin

In Vitro: The cell lines differ in their relative expression of Tpm3.1 as well as in the expression of other isoforms. After determing the IC₅₀ concentrations for TR100 and ATM-3507 (CHLA-20: 4.99±0.45 μM, CHP-134: 3.83±0.67 μM, CHLA-90: 6.84±2.37 μM, SK-N-BE(2): 5.00±0.42 μM) in each of the neuroblastoma cell lines, combinations of tropomyosin inhibitors plus Vincristine are tested at levels of each drug alone that kill less than 50% of the neuroblastoma cells. The combinations of both tropomyosin inhibitors plus Vincristine are completely cytotoxic in CHLA-20 cells. All 4 cell lines show some degree of synergy as determined by the Chou–Talalay method. The effect is not limited to the vinca alkaloids as a similar combination efficacy using paclitaxel plus TR100 or ATM-3507.

In Vivo: The maximal tolerance dose (MTD) for TR100 and ATM-3507 is 60 and 150 mg/kg, respectively. It is found that a significant inhibition of tumor growth and prolongation of animal survival using either combination compared with each monotherapy. The median survival of mice increased from 18 days for mice treated with ATM-3507 to more than 49 days for mice treated with the combination. It is also found that twice weekly intravenous administration of ATM-3507 also show combination efficacy. The impact of each treatment or the combination on body weight is minimal. Drug levels are measured following the intravenous administration of ATM-3507 at 30 mg/kg in Balb/c mice (n=3 per time point). The mean half-life of ATM-3507 is 5.01 hrs for the terminal elimination phase. The mean AUC_0-t in the plasma is 14,548 ng/h/mL. The C_max of ATM-3507 is 5,758 ng/mL and the the t_1/2 is 5.01 h. The observed plasma clearance and volume of distribution at steady state of ATM-3507 is 33.8 mL/min/kg and 7.23 L/kg, respectively.

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