Neurosurgery and Neuro-Oncology Department, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Clinical College, Jilin University, Changchun, China.
Bioengineered. 2022 May;13(5):12003-12020. doi: 10.1080/21655979.2021.2011631.
Despite great progress, the current cancer treatments often have obvious toxicity and side effects. and a poor prognosis (some patients). One of the reasons for the poor prognosis is that certain enzymes prevent anticancer drugs from killing tumor cells. AKT1 is involved in regulating PI3K/AKT/mTOR, a tumor-generating pathway. Ipatasertib, a highly selective inhibitor of AKT1, is widely used in the treatment of tumors. In this study, many structural and biochemical methodswere used to find better AKT1(Threonine Kinase 1) inhibitors, which laid a foundation for the further development of AKT1 inhibitors and provided new drugs for the treatment of tumors. ZINC15 database and Discovery Studio 4.5, a computer-aided drug screening software with many modules (LibDock for virtual screening, ADME (Absorption, Distribution, Metabolism, Excretion) and TOPKAT (toxicity prediction module) for the toxicity and properties analysis, and MD simulation for stability prediction), were employed. CCK8 assay, ELISA assay genicity and higher tolerance to cytochrome P4502D6. MD simulations indicated they could bind with AKT1 stably in the natural environment. The cell experiment and specific assay for AKT1 inhibition showed they could inhibit the proliferation and AKT1 expression of MG63 cells (Osteosarcoma cells). Moreover, these novel compounds with structural modifications can be potential contributors that lead to further rational drug design for targeting AKT1.AKT1, AKT Serine/Threonine Kinase 1; ADME, absorption, distribution, metabolism, excretion; TOPKAT, toxicity prediction by Computer assisted technology; CCK8, Cell Counting Kit 8; ELISA, Enzyme-linked immunosorbent assay; CYP2D6, cytochrome P4502D6 inhibition; GBM, Glioblastoma; AGC kinase, protein kinase A, G, and C families (PKA, PKC, PKG); PKB, protein kinase B; PAM pathway, PI3K/AKT/mTOR pathway; OS, overall survival; PFS, progression-free survival; LD50, lethal dose half in rats; LOAEL, lowest observed adverse effect level; NPT, normal pressure and temperature; PME, particle mesh Ewald; LINCS, linear constraint solver; RMSD, root-mean-square deviation; BBB, blood-brain barrier; DS, Discovery Studio; DTP, Developmental toxicity potential; PPB, Plasma protein binding; MTD, Maximum Tolerated Dosage; AB, Aerobic Biodegradability; NTP, US. National Toxicology Program; DTP, developmental toxicity potential.
尽管取得了很大的进展，但目前的癌症治疗方法往往具有明显的毒性和副作用，且预后较差（某些患者）。预后较差的原因之一是某些酶阻止了抗癌药物杀死肿瘤细胞。AKT1 参与调节 PI3K/AKT/mTOR，这是一种致癌途径。伊帕替膦（Ipatasertib）是 AKT1 的一种高选择性抑制剂，广泛用于肿瘤治疗。在这项研究中，使用了许多结构和生化方法来寻找更好的 AKT1（苏氨酸激酶 1）抑制剂，为 AKT1 抑制剂的进一步发展奠定了基础，并为肿瘤治疗提供了新的药物。ZINC15 数据库和 Discovery Studio 4.5，一种具有许多模块的计算机辅助药物筛选软件（用于虚拟筛选的 LibDock、ADME（吸收、分布、代谢、排泄）和用于毒性和特性分析的 TOPKAT、用于稳定性预测的 MD 模拟），被采用。CCK8 测定、ELISA 测定、基因毒性和对细胞色素 P4502D6 的更高耐受性。MD 模拟表明，它们可以在自然环境中稳定地与 AKT1 结合。细胞实验和 AKT1 抑制的特异性测定表明，它们可以抑制 MG63 细胞（骨肉瘤细胞）的增殖和 AKT1 表达。此外，这些具有结构修饰的新型化合物可以作为潜在的贡献者，进一步促进针对 AKT1 的合理药物设计。AKT1，AKT 丝氨酸/苏氨酸激酶 1；ADME，吸收、分布、代谢、排泄；TOPKAT，计算机辅助毒性预测技术；CCK8，细胞计数试剂盒 8；ELISA，酶联免疫吸附测定；CYP2D6，细胞色素 P4502D6 抑制；GBM，胶质母细胞瘤；AGC 激酶，蛋白激酶 A、G 和 C 家族（PKA、PKC、PKG）；PKB，蛋白激酶 B；PAM 途径，PI3K/AKT/mTOR 途径；OS，总生存期；PFS，无进展生存期；LD50，大鼠半数致死剂量；LOAEL，最低观察到的不良效应水平；NPT，正常压力和温度；PME，粒子网格 Ewald；LINCS，线性约束求解器；RMSD，均方根偏差；BBB，血脑屏障；DS，Discovery Studio；DTP，发育毒性潜力；PPB，血浆蛋白结合；MTD，最大耐受剂量；AB，需氧生物降解性；NTP，美国。国家毒理学计划；DTP，发育毒性潜力。
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