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AZD-5991

CAS No. : 2143061-81-6

MCE 站：AZD-5991

产品活性：AZD-5991 是一种有效的选择性 Mcl-1 抑制剂，FRET 实验检测的 IC₅₀ 为 0.7 nM， SPR 实验检测的 K_d 为 0.17 nM。

研究领域：Apoptosis

作用靶点：Bcl-2 Family

In Vitro: The selectivity of AZD-5991 is evaluated against pro-survival Bcl-2 family members using FRET assays. AZD-5991 is selective for Mcl-1 (IC₅₀ 0.72?nM, K_i=200?pM) vs. Bcl-2 (IC₅₀=20??M, K_i=6.8??M), Bcl-xL (IC₅₀=36??M, K_i=18??M), Bcl-w (IC₅₀=49??M, K_i=25??M), and Bfl-1 (IC₅₀=24??M, K_i=12??M). MOLP-8, MV4-11, and NCI-H23 cells are treated with AZD5991 (EC₅₀=0.033, 0.024, 0.19??M, respectively).AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 reduces the levels of Mcl-1 protein in AZD5991-sensitive but not in AZD5991-resistant MM cell lines further supporting the notion that activation of caspases by AZD5991 reduces Mcl-1 protein levels in AZD5991-sensitive cell lines.

In Vivo: A single intravenous (i.v.) dose of AZD5991 leads to a dose-dependent antitumor effect ranging from tumor growth inhibition (TGI) to tumor regression (TR). Ten days after treatment, AZD5991 shows 52% and 93% TGI (p<0.0001) at 10 and 30?mg/kg, respectively. At the same time point, AZD5991 at 60?mg/kg leads to 99% TR with no detectable tumors in 6 out of 7 mice, while complete TR is seen in 7 out of 7 mice in the 100?mg/kg dose group. AZD5991 also shows a dose-dependent duration of response with tumors in the 100?mg/kg group growing back later than those in the 60?mg/kg group. The magnitude of in vivo tumor efficacy is correlated with activation of caspase-3 in the tumor and concentration of AZD5991 in plasma. Treatment with AZD5991 was well tolerated at all dose levels with no significant body weight loss. A single dose of AZD5991 36 days after the first dose causes tumor regression in 4 out of 4 mice. In mice dosed with AZD5991 at 100?mg/kg on day 0 and day 1, tumors grow back later than those dosed with a single dose of AZD5991 at the same dose level.

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