State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , China.
J Med Chem. 2018 Jul 26;61(14):6087-6109. doi: 10.1021/acs.jmedchem.8b00416. Epub 2018 Jul 9.
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.
PI3K 信号通路的过度激活是癌症中最常见的改变之一，这促使人们积极努力开发针对该通路的新型癌症治疗药物。在这项工作中，我们通过杂交和随后的骨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。通过优化得到了几个有前景的化合物（例如 19、20、37 和 43），具有纳摩尔级别的 PI3K 抑制活性、显著的抗增殖活性、良好的 PK 特性和强大的体内抗肿瘤疗效。更有趣的是，与化合物 19 和 20 相比，化合物 37 和 43 在原位胶质母细胞瘤异种移植模型中显示出了更好的脑穿透和体内疗效。此外，还进行了包括 hERG 通道抑制、AMES、CYP450 抑制和单次毒性在内的初步安全性评估，以表征它们的毒理学特性。
