AZD8055

AZD8055是一种选择性mTOR激酶抑制剂，IC50值为0.8 nM[1]，可与ATP竞争性结合mTOR的ATP结合裂口。与密切相关的激酶PI3K亚型和ATM/DNA-PK相比，对mTOR具有约1000倍的选择性。此外，10 μM AZD8055对其他260种激酶无显著活性[1]。

临床前研究表明AZD8055具有潜在抗肿瘤活性。mTOR磷酸化和活化转录因子，从而调节细胞生长、增殖、运动和存活。AZD8055可抑制mTORC1和mTORC2复合体下游的信号[1]。AZD8055可抑制肺癌、宫颈癌和喉癌以及急性髓性白血病细胞系的增殖[1-4]。异种移植模型研究表明AZD8055可抑制胶质母细胞瘤、乳腺癌、肺癌、结肠癌、前列腺癌、子宫癌和头颈癌的肿瘤生长[1，5]。此外，AZD8055还可增强HDAC 抑制剂和MEK抑制剂的功效[6-8]。AZD8055已在I期临床实验中进行检测，具有最小的临床获益[9，10]。

参考文献：
[1] Chresta CM, Davies BR, Hickson I 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: 288-298.
[2] Li S, Li Y, Hu R et al.  The mTOR inhibitor AZD8055 inhibits proliferation and glycolysis in cervical cancer cells. Oncol Lett 2013; 5: 717-721.
[3] Willems L, Chapuis N, Puissant A et al.  The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia. Leukemia 2012; 26: 1195-1202.
[4] Zhao L, Teng B, Wen L et al.  mTOR inhibitor AZD8055 inhibits proliferation and induces apoptosis in laryngeal carcinoma. Int J Clin Exp Med 2014; 7: 337-347.
[5] Li Q, Song XM, Ji YY et al.  The dual mTORC1 and mTORC2 inhibitor AZD8055 inhibits head and neck squamous cell carcinoma cell growth in vivo and in vitro. Biochem Biophys Res Commun 2013; 440: 701-706.
[6] Shao H, Gao C, Tang H et al.  Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo. J Hepatol 2012; 56: 176-183.
[7] Holt SV, Logie A, Davies BR et al.  Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055). Cancer Res 2012; 72: 1804-1813.
[8] Renshaw J, Taylor KR, Bishop R et al.  Dual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo. Clin Cancer Res 2013; 19: 5940-5951.
[9] Asahina H, Nokihara H, Yamamoto N et al.  Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; a dose-finding phase I study. Invest New Drugs 2013; 31: 677-684.
[10] Naing A, Aghajanian C, Raymond E et al.  Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br J Cancer 2012; 107: 1093-1099.