Background
AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor, with IC50 values of 0.4, 5, and 1.9nM for PIM1, PIM2, and PIM3, respectively[1,2]. AZD1208 is a thiazolidine that is known for its anti-cancer activity[3]
AZD1208 has anti-adipogenic and lipolytic effects on 3T3-L1 adipocytes through control of the expression and/or phosphorylation levels of PPAR-c, C/EBP-a, FAS, ACC, perilipin A, STAT-3, AMPK and HSL, that advocate AZD1208 as a potential therapeutics for the treatment of obesity[3]. AZD1208 resulted in suppression of mTOR signaling, including inhibition of protein phosphorylation of mTOR(Ser2448), p70S6K(Thr389), S6(Ser235/236) and 4E-BP1(Ser65)[4]. Treatment with AZD1208 alone induced considerable cell death through autophagy in gastric cancer cells. AZD1208 combines with an Akt inhibitor (AZD5363) showed synergistic antitumor effects through regulation of the DNA damage repair pathway[5]
AZD1208 dose-dependent inhibits the growth of MOLM-16 xenograft tumors in vivo. Treatment with 10mg/kg or 30mg/kg of AZD1208 led to 89% tumor growth inhibition or slight regression, respectively[2]. AZD1208 decreased the growth of tumors comprised of hepatoblastoma CD133-enriched cells, with 57% of the animals experiencing complete tumor regression in a vivo xenograft model[6]. AZD1208 was generally tolerated in patients with heavily pretreated AML (120–900 mg dose range) and advanced solid malignancies (120–800 mg dose range). AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance[6]
参考文献:
[1]. Cervantes-Gomez F, Stellrecht CM, et al. PIM kinase inhibitor, AZD1208, inhibits protein translation and induces autophagy in primary chronic lymphocytic leukemia cells. Oncotarget. 2019;10(29):2793-2809. Published 2019 Apr 19.
[2]. Keeton EK, McEachern K, et al. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood. 2014;123(6):905-913
[3]. Park YK, Obiang-Obounou BW, et al. AZD1208, a pan-Pim kinase inhibitor, inhibits adipogenesis and induces lipolysis in 3T3-L1 adipocytes. J Cell Mol Med. 2018;22(4):2488-2497.
[4]. Chen LS, Yang JY, et al. Protein profiling identifies mTOR pathway modulation and cytostatic effects of Pim kinase inhibitor, AZD1208, in acute myeloid leukemia. Leuk Lymphoma. 2016;57(12):2863-2873.
[5]. Lee M, Lee KH, et al. Pan-Pim Kinase Inhibitor AZD1208 Suppresses Tumor Growth and Synergistically Interacts with Akt Inhibition in Gastric Cancer Cells. Cancer Res Treat. 2019;51(2):451-463.
[6]. Stafman LL, Williams AP, et al. Targeting PIM Kinases Affects Maintenance of CD133 Tumor Cell Population in Hepatoblastoma. Transl Oncol. 2019;12(2):200-208.
[7]. Cortes J, Tamura K, et al. Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers. Br J Cancer. 2018;118(11):1425-1433.
AZD1208 是一种有效、高选择性且可口服的 Pim 激酶抑制剂，对 PIM1、PIM2 和 PIM3 的 IC50 值分别为 0.4、5 和 1.9nM[ 1,2]。 AZD1208 是一种以抗癌活性着称的噻唑烷[3]
AZD1208 通过控制 PPAR-c、C/EBP-a、FAS、ACC、perilipin A、STAT-3、AMPK 和HSL，提倡 AZD1208 作为治疗肥胖症的潜在疗法[3]。 AZD1208 抑制 mTOR 信号，包括抑制 mTOR(Ser2448)、p70S6K(Thr389)、S6(Ser235/236) 和 4E-BP1(Ser65)[4] 的蛋白磷酸化。单独使用 AZD1208 治疗可通过胃癌细胞自噬诱导大量细胞死亡。 AZD1208 与 Akt 抑制剂 (AZD5363) 结合通过调节 DNA 损伤修复途径显示出协同抗肿瘤作用[5]
AZD1208 在体内剂量依赖性抑制 MOLM-16 异种移植肿瘤的生长。用 10mg/kg 或 30mg/kg 的 AZD1208 治疗分别导致 89% 的肿瘤生长抑制或轻微消退[2]。 AZD1208 减少了由肝母细胞瘤 CD133 富集细胞组成的肿瘤的生长，57% 的动物在体内异种移植模型中经历了完全的肿瘤消退[6]。 AZD1208 在经过大量预处理的 AML（120-900 mg 剂量范围）和晚期实体恶性肿瘤（120-800 mg 剂量范围）患者中普遍耐受。 AZD1208 在多次给药后增加 CYP3A4 活性，从而增加药物清除率[6]
Protocol
| Kinase experiment [1]: |
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Preparation Method
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To determine inhibition constants (Ki), 50% inhibition concentration (IC50) values were acquired at a series of ATP concentrations and compound doses with 1nM enzyme and 1.5mM full-length BAD substrate in 50mM N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid, 1mM dithiothreitol, 0.01% Tween 20, 50mg/mL bovine serum albumin, and 10mM MgCl2
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Reaction Conditions
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1nM enzyme
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Applications
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AZD1208 is a potent ATP-competitive inhibitor of all three Pim kinase isoforms. The Ki values were determined to be 0.1nM for Pim-1, 1.92nM for Pim-2, and 0.4nM for Pim-3. In enzymatic assays carried out at a concentration of ATP that leads to half-maximal reaction velocity, AZD1208 inhibited kinase activity with an IC50 of 0.4nM for Pim-1, 5.0nM for Pim-2, and 1.9nM for Pim-3. In enzyme assays using 5mM ATP, the high end of physiologic ATP concentration in human cells, the IC50 values were 2.6nM for Pim-1, 164nM for Pim-2, and 17nM for Pim-3.
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| Cell experiment [2]: |
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Cell lines
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MEC-1 cell line (derived from a patient with B-chronic lymphocytic leukemia)
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Preparation Method
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The cells were maintained in RPMI 1640 medium supplemented with 10% FBS serum with 5% carbon dioxide at 37℃ and maintained at 106 cells/mL.
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Reaction Conditions
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3 and 10μM AZD1208
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Applications
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MEC-1 cells treated with either AZD1208 concentration had less cell growth at all three time points compared to the MEC-1 cells treated with DMSO. At 48 hours, 3μM AZD1208 and at 72 hours both 3 and 10μM AZD1208 were significantly different than DMSO control. The cell death rate in MEC-1 cells treated with 10μM AZD1208 ranged from 6% to 12% across all three time points.
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| Animal experiment [3]: |
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Animal models
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Six-week-old female BALB/c nude mice
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Preparation Method
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The mice were injected subcutaneously in the right flank with 7×107 of SNU-638 cells in 100μL of PBS. After implantation of the tumor cells, the tumor sizes were measured every other day, and the body weight of each mouse was determined twice per week. The mice were randomly divided into two groups (five mice per group) when tumor volumes reached 200mm3, and 45mg/kg of AZD1208 were administered via oral gavage once daily for 28 consecutive days. The control group was treated with vehicle alone (1mM histidine, 130mM Glycine, 5% sucrose in water).
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Dosage form
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45 mg/kg，oral gavage once daily for 28 consecutive days
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Applications
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AZD1208 significantly delayed tumor growth. The doubling time of tumor volume with vehicle treatment was 17 days, while the time to 2-fold increase of tumor volume with AZD1208 treatment was observed after 31 days, which supports the delay of tumor growth by AZD1208 treatment. Furthermore, AZD1208 treated mice showed lower Ki-67 expression, suggesting lower proliferation ability compared with non-treated mice. These data demonstrated the antitumor effects of AZD1208 in a gastric cancer model.
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参考文献:
[1]. Keeton EK, McEachern K, et al. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood. 2014;123(6):905-913.
[2]. Cervantes-Gomez F, Stellrecht CM, et al. PIM kinase inhibitor, AZD1208, inhibits protein translation and induces autophagy in primary chronic lymphocytic leukemia cells. Oncotarget. 2019;10(29):2793-2809. Published 2019 Apr 19.
[3]. Lee M, Lee KH, et al. Pan-Pim Kinase Inhibitor AZD1208 Suppresses Tumor Growth and Synergistically Interacts with Akt Inhibition in Gastric Cancer Cells. Cancer Res Treat. 2019;51(2):451-463.
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