AZD8055

AZD8055 is a new ATP-competitive mTOR inhibitor with an IC₅₀ of 0.8 nmol/L and a K_i of 1.3 nmol/L^[1]. mTOR is a serine/threonine kinase, and AZD8055 is a potent mTORC1/mTORC2 dual inhibitor^[2]. AZD8055 significantly inhibits the phosphorylation of Akt^Ser473 and induces apoptosis ^[3].

In vitro, AZD8055 (5 nmol/L) resulted in 70% to 80% inhibition of p70S6K in MCF-7 and HEK cells. AZD8055 also inhibited a variety of cancer cells (including U87MG, BT474c, A549, Calu-3, LoVo, SW620 , PC3 and MES-SA, etc.) show obvious anti-cancer activity^[1]. AZD8055 (0.1 and 1uM) significantly inhibits the activity of mTORC1 and mTORC2, thereby inhibiting Akt^Ser473 phosphorylation in human neuroblastoma cell lines, and also inhibits cell growth in vitro by inducing autophagy, apoptosis and cell cycle arrest ^[2]. The IC₅₀ of AZD8055 against several laryngeal cancer cell lines are: UM-SCC-98 (~40μM), UM-SCC-12 (~23μM), and UM-SCC-11A (~8μM) ^[4].

In vivo, AZD8055 (5 mg/kg) was injected intraperitoneally every other day for xenograft model mice for eight times in total, which inhibited tumor growth and had no obvious adverse effects on the body weight of the mice^[2]. Intraperitoneal injection of AZD8055 (10 mg/kg) into mice transiently increases plasma insulin levels 3-fold, induces insulin resistance in mice, and impairs mTOR signaling in insulin-responsive tissues. It also causes increased lipid oxidation and glucose Intolerance^[5]. Oral treatment of PTEN^+/−LKB1^+/hypo mice with AZD8055 (20mg/kg) for 42 days induced a reduction of approximately 40% in tumor volume and simultaneously ablated the phosphorylation of AKT, S6K and SGK protein kinases^[6].

References:

[1] Chresta CM, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res, 2010, 70(1), 288-298.

[2] Xu D Q , Toyoda H , Yuan X J ,et al.Anti-tumor effect of AZD8055 against neuroblastoma cells in vitro and in vivo[J].Experimental Cell Research, 2018, 365(2).

[3] Kawata T, Tada K, Kobayashi M, et al. Dual inhibition of the mTORC 1 and mTORC 2 signaling pathways is a promising therapeutic target for adult T‐cell leukemia[J]. Cancer science, 2018, 109(1): 103-111.

[4] Gobin C, Chang M, Lattimore C C, et al. Exploring the association between miR-9-5p levels and the mTORC1/mTORC2 pathway in laryngeal cancer cell lines[J]. Cancer Research, 2024, 84(6_Supplement): 5696-5696.

[5] Kleinert M, Sylow L, Fazakerley D J, et al. Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo[J]. Molecular metabolism, 2014, 3(6): 630-641.

[6] Garcia-Martinez J M, Wullschleger S, Preston G, et al. Effect of PI3K-and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice[J]. British journal of cancer, 2011, 104(7): 1116-1125.

AZD8055是一种新型的ATP竞争性mTOR抑制剂，IC₅₀ 为0.8 nmol/L，K_i为1.3 nmol/L^[1]。mTOR是一种丝氨酸/苏氨酸激酶，AZD8055是有效的mTORC1/mTORC2双重抑制剂^[2]。AZD8055明显抑制Akt^Ser473的磷酸化并诱导细胞凋亡^[3]。

在体外，AZD8055（5nmol/L）导致MCF-7和HEK细胞中p70S6K的抑制率为70%至80%，AZD8055还对多种癌细胞（包括U87MG， BT474c， A549， Calu-3， LoVo， SW620，PC3和MES-SA等）显示出明显的抗癌活性^[1]。AZD8055（0.1 and 1uM）显着抑制mTORC1和mTORC2的活性，从而抑制人神经母细胞瘤细胞系中的 Akt^Ser473磷酸化，还通过诱导自噬、细胞凋亡和细胞周期停滞来抑制体外细胞生长^[2]。 AZD8055对几种喉癌细胞系的IC₅₀分别为：UM-SCC-98（~40μM）、UM-SCC-12 （~23μM）、UM-SCC-11A （~8μM）^[4]。

在体内，AZD8055（5mg/kg）每隔一天腹腔注射治疗异种移植模型小鼠，共八次，可以抑制肿瘤生长，且对小鼠体重观察没有明显的不良反应^[2]。AZD8055（10mg/kg） 腹腔注射治疗小鼠，会短暂地使血浆胰岛素水平升高3倍，诱导小鼠胰岛素抵抗，并损害胰岛素反应组织中的mTOR 信号传导，还会引起脂质氧化增加和葡萄糖耐受不良^[5]。AZD8055（20mg/kg）口服治疗PTEN^+/−LKB1^+/hypo小鼠42天，诱导肿瘤体积减少约40%，同时消融 AKT、S6K和SGK蛋白激酶的磷酸化^[6]。