Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China.
Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, Lianyungang 222047, China.
Eur J Pharm Sci. 2017 Dec 15;110:51-61. doi: 10.1016/j.ejps.2017.01.021. Epub 2017 Jan 21.
The discovery and development of a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor SHR1258 (pyrotinib) for the treatment of HER2-postive breast cancer is presented. The structure-activity relationship of lead series and their pharmacokinetic properties were evaluated to identify the potential candidates for further in vivo efficacy studies and preclinical safety assessments. Metabolic pathway and drug-drug interaction were also investigated in preclinical settings. In particular, major metabolites in human and animal species were assessed with regard to potential toxicity or off-target side effects. Overall, the potent and selective EGFR/HER2 dual inhibitor, pyrotinib, displayed robust anti-tumor effects on HER2-overexpressing xenograft models and sufficiently safety windows in animals as well as favorable pharmacokinetic properties in human, which substantially ensures current clinical development. Finally, recent advances of pyrotinib in clinical studies are highlighted with very encouraging outcomes in patients with HER2-postive advanced breast cancer.
本文介绍了一种新型不可逆的 EGFR/HER2 双酪氨酸激酶抑制剂 SHR1258（吡咯替尼）的发现和开发，用于治疗 HER2 阳性乳腺癌。评估了先导化合物系列的构效关系及其药代动力学特性，以确定具有进一步体内疗效研究和临床前安全性评估潜力的候选药物。还在临床前环境中研究了代谢途径和药物相互作用。特别是，评估了人类和动物物种中的主要代谢物，以评估其潜在毒性或脱靶副作用。总的来说，强效和选择性的 EGFR/HER2 双重抑制剂吡咯替尼在 HER2 过表达的异种移植模型中显示出强大的抗肿瘤作用，在动物中具有足够的安全性窗口，以及在人体中良好的药代动力学特性，这为其临床开发提供了有力保障。最后，本文重点介绍了吡咯替尼在临床研究中的最新进展，在 HER2 阳性晚期乳腺癌患者中取得了非常令人鼓舞的结果。
