AZD5363 is a selective inhibitor of the protein kinases AKT1, AKT2, and AKT3, with IC₅₀ values of 3, 7, and 7nM, respectively[1]. AZD5363 targets the PI3K/AKT/mTOR signaling pathway and has demonstrated anti-tumor activity and potential therapeutic applications in various cancers[2]. PI3K/AKT/mTOR pathway is frequently dysregulated in many cancers, leading to increased cell survival, proliferation, and resistance to apoptosis[3]. AZD5363 is currently under regulatory review for the treatment of HR-positive, HER2-negative breast cancer and is in Phase III clinical development. AZD5363 has been used to treat triple-negative breast cancer, castration-resistant prostate cancer, and hormone-sensitive prostate cancer, either as monotherapy or in combination with other anticancer drugs[4].
In vitro, AZD5363 (0, 1, 2, 5µM) treatment of breast cancer stem cell spheres (BCSCs) derived from triple-negative breast cancer MDA-MB-231 cells significantly downregulated the expression of the mitochondrial fusion protein Mitofusin 1, decreased mitochondrial activity, and induced apoptosis. Moreover, AZD5363 in combination with doxorubicin (Doxo, 50nM) significantly suppressed the expression of the stemness markers CD44 and CD133 induced by Doxo, enhanced Doxo-induced apoptosis, and reduced chemoresistance of BCSCs to Doxo[5]. AZD5363 (2.5–20µM) alone or in combination with low concentrations of salinomycin (0.5–1µM) significantly enhanced the sensitivity of Hs578T breast cancer cells to salinomycin, as evidenced by reduced cell proliferation and increased apoptosis. The combination treatment increased apoptosis via S-phase arrest, with a significant increase in the proportion of early apoptotic cells[6].
In vivo, AZD5363 (70mg/kg) was administered via intravenous injection to treat a glioblastoma (GBM) model in nude mice, once a week for four doses. Mice received 2.5Gy of radiotherapy 24 hours after AZD5363 treatment. The combination treatment significantly prolonged the survival of the mice and significantly reduced the number of cancer stem cells (CSCs) in the tumors[7]. AZD5363 (150mg/kg/day) was administered orally to mice harboring AKT1E17K-mutant meningiomas. AZD5363 significantly inhibited meningioma cell proliferation, reduced tumor size, and prolonged mouse survival[8].
References:
[1] Davies BR, Greenwood H, Dudley P, et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 2012 Apr;11(4):873-87.
[2] Alves CL, Ditzel HJ. Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer. Int J Mol Sci. 2023 Feb 24;24(5):4522.
[3] Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023 Aug 18;22(1):138.
[4] Shirley M. Capivasertib: First Approval. Drugs. 2024 Mar;84(3):337-346.
[5] Fu Y, Dong W, Xu Y, et al. Targeting mitochondrial dynamics by AZD5363 in triple-negative breast cancer MDA-MB-231 cell-derived spheres. Naunyn Schmiedebergs Arch Pharmacol. 2023 Oct;396(10):2545-2553.
[6] Choi AR, Jung MJ, Kim JH, et al. Co-treatment of Salinomycin Sensitizes AZD5363-treated Cancer Cells Through Increased Apoptosis. Anticancer Res. 2015 Sep;35(9):4741-7.
[7] Ding X, Liang J, Sharko AC, et al. Mediator kinase inhibitors suppress triple-negative breast cancer growth and extend tumor suppression by mTOR and AKT inhibitors. Proc Natl Acad Sci U S A. 2024 Nov 19;121(47):e2414501121.
[8] John P, Waldt N, Liebich J, et al. AKT1E17K -mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363. Neuropathol Appl Neurobiol. 2022 Feb;48(2):e12780.
AZD5363是一种选择性抑制蛋白激酶Akt1、Akt2和Akt3的小分子化合物，IC₅₀值分别为3nM、7nM和7nM[1]。AZD536靶向PI3K/Akt/mTOR信号通路，在多种癌症中显示出抗肿瘤活性[2]。PI3K/Akt/mTOR信号通路在许多癌症中经常失调，导致细胞存活、增殖增加以及对凋亡的抵抗[3]。AZD5363正在接受关于治疗HR阳性、HER2阴性乳腺癌的监管审查，并处于III期临床开发中，AZD5363已经用于治疗（与其他抗癌药物联合使用）治疗三阴性乳腺癌、去势抵抗性前列腺癌和激素敏感性前列腺癌[4]。
在体外，AZD5363（0、1、2、5μM）处理三阴性乳腺癌MDA-MB-231细胞衍生的干细胞球（BCSCs），显著抑制了线粒体融合蛋白Mitofusin 1的表达，降低了线粒体活性，并诱导了细胞凋亡。此外，AZD5363联合阿霉素（Doxo，50nM）处理BCSCs，可显著抑制Doxo诱导的干细胞标志物CD44和CD133的表达，增强Doxo诱导的细胞凋亡，并降低BCSCs对Doxo的耐药性 [5]。AZD5363（2.5-20μM）单独或与低浓度盐霉素（Salinomycin，0.5-1μM）联合处理Hs578T乳腺癌细胞，AZD5363显著增强了细胞对Salinomycin的敏感性，表现为细胞增殖减少，细胞凋亡增加。联合处理通过S期阻滞增加凋亡，且早期凋亡细胞比例显著增加[6]。
在体内，AZD5363（70mg/kg）通过静脉注射治疗携带胶质母细胞瘤（GBM）的裸鼠模型，每周一次，共4次。小鼠在AZD5363给药后24小时接受2.5Gy的放射治疗。联合治疗显著延长了小鼠的生存期，并显著降低了肿瘤中癌症干细胞（CSC）的数量[7]。AZD5363（150mg/kg/天）通过口服给药的方式治疗携带AKT1E17K突变型脑膜瘤的小鼠。AZD5363显著抑制了脑膜瘤细胞的增殖，减少了肿瘤大小，并延长了小鼠的生存期[8]。