Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment,Journal of Medicinal Chemistry

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Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-06-21 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00416
Songwen Lin _{1,

2} , Chunyang Wang ₁ , Ming Ji ₁ , Deyu Wu _{1,

2} , Yuanhao Lv ₁ , Kehui Zhang _{1,

2} , Yi Dong _{1,

2} , Jing Jin ₁ , Jiajing Chen _{1,

2} , Jingbo Zhang _{1,

2} , Li Sheng ₃ , Yan Li ₃ , Xiaoguang Chen ₁ , Heng Xu _{1,

2}

Affiliation

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.

中文翻译：

发现和优化2-氨基-4-甲基喹唑啉衍生物作为治疗癌症的高效磷脂酰肌醇3-激酶抑制剂

磷脂酰肌醇3激酶（PI3K）信号的增加是癌症中最常见的变化之一，促使人们投入大量精力开发针对该途径的新型癌症疗法。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型的2-氨基-4-甲基喹唑啉衍生物，它们是高效的I类PI3K抑制剂。先导物优化导致了几个有前途的化合物（例如，19，20，37，和43）以纳摩尔效力PI3K，突出的抗增殖活性，有利的PK曲线，以及在体内抗肿瘤效力的鲁棒性。更有趣的是，与19和20相比，37和图43显示了在原位胶质母细胞瘤异种移植模型中改善的脑渗透和体内功效。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，以表征其毒理学特性。

更新日期：2018-06-21

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