title: Discovery and development of pyrotinib: A novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer.
abstract: 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.
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China. Electronic address: lix@shhrp.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, Lianyungang 222047, China. Electronic address: yangcy@shhrp.com.
authors.forename: Changyong
authors.initials: C
authors.lastname: Yang
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China. Electronic address: wanh@shhrp.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.affiliation: Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, Lianyungang 222047, China. Electronic address: zhangge@shhrp.com.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China. Electronic address: fengj@shhrp.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China. Electronic address: zhangl@shhrp.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: xychen@simm.ac.cn.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: dfzhong@simm.ac.cn.
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: lglou@mail.shcnc.ac.cn.
authors.forename: Liguang
authors.initials: L
authors.lastname: Lou
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China. Electronic address: taowk@shhrp.com.
authors.forename: Weikang
authors.initials: W
authors.lastname: Tao
authors.affiliation: Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, Lianyungang 222047, China; China Pharmaceutical University, Jiangsu Key Laboratory of Drug Design and Optimization, Nanjing 210009, China. Electronic address: zhanglianshan@hrs.com.cn.
authors.forename: Lianshan
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000178:Acrylamides / Q000494:pharmacology* / Q000627:therapeutic use; D000634:Aminoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D064593:Heterografts; D006801:Humans; D053858:Metabolic Networks and Pathways; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C000622954:pyrotinib
keywords: Clinical; Drug metabolism; HER2-postive breast cancer; Irreversible EGFR/HER2 dual tyrosine kinase inhibitor; Preclinical; Pyrotinib; Safety