AZD1208

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]

References:
[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]