Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment
Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment
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DOI：
10.1021/acs.jmedchem.8b00416
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发表时间：
2018-07-26
影响因子：
7.3
通讯作者：
Xu, Heng
中科院分区：
文献类型：
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作者：
Lin, Songwen;Wang, Chunyang;Xu, Heng
增加的磷脂酰肌醇3-激酶（PI3K）信号是癌症中最常见的改变之一，促使人们努力开发针对这一途径的新癌症治疗方法。在这项工作中，我们通过杂交和随后的支架跳跃方法发现了一系列新的2-氨基-4-甲基喹唑啉衍生物，它们是高效的I类PI3K抑制剂。引线优化得到了几种有前景的化合物（如19、20、37和43），它们具有纳米摩尔PI3K的效力、突出的抗增殖活性、有利的PK谱和强大的体内抗肿瘤功效。更有趣的是，与19和20相比，37和43在原位胶质母细胞瘤异种移植模型中表现出更好的脑穿透和体内疗效。此外，进行了初步的安全性评估，包括hERG通道抑制、AMES、CYP450抑制和单剂量毒性，以表征它们的毒理学特性。
Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.