2. Academic Validation
  3. Discovery and development of pyrotinib: A novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer

Discovery and development of pyrotinib: A novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer

  • Eur J Pharm Sci. 2017 Dec 15;110:51-61. doi: 10.1016/j.ejps.2017.01.021.
Xin Li 1,  Changyong Yang 2,  Hong Wan 3,  Ge Zhang 4,  Jun Feng 5,  Lei Zhang 6,  Xiaoyan Chen 7,  Dafang Zhong 8,  Liguang Lou 9,  Weikang Tao 10,  Lianshan Zhang 11
Affiliations

Affiliations

  • 1 Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China. Electronic address: lix@shhrp.com.
  • 2 Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, Lianyungang 222047, China. Electronic address: yangcy@shhrp.com.
  • 3 Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China. Electronic address: wanh@shhrp.com.
  • 4 Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, Lianyungang 222047, China. Electronic address: zhangge@shhrp.com.
  • 5 Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China. Electronic address: fengj@shhrp.com.
  • 6 Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China. Electronic address: zhangl@shhrp.com.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: xychen@simm.ac.cn.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: dfzhong@simm.ac.cn.
  • 9 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.
  • 10 Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China. Electronic address: taowk@shhrp.com.
  • 11 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.
PMID: 28115222 DOI: 10.1016/j.ejps.2017.01.021
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.

Keywords

Clinical; Drug metabolism; HER2-postive breast cancer; Irreversible EGFR/HER2 dual tyrosine kinase inhibitor; Preclinical; Pyrotinib; Safety.

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