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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Pyrotinib covalently binds to ATP binding sites in intracellular kinase regions of EGFR, HER2 and HER4, preventing homodimer formation, thereby irreversibly inhibiting autophosphorylation, blocking activation of downstream signaling pathways, and inhibiting tumor cell growth.
“Similarly, as the third-generation EGFR TKI, pyrotinib covalently binds to ATP binding sites in intracellular kinase regions of EGFR, HER2 and HER4, preventing homodimer formation, thereby irreversibly inhibiting autophosphorylation, blocking activation of downstream signaling pathways, and inhibiting tumor cell growth.156–158”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [156]
The citation lists haven’t been fetched yet
References 41 · Cited by 227
- Authors
- Li, X., Yang, C., Wan, H., Zhang, G., Feng, J., Zhang, L., Chen, X., Zhong, D., Lou, L., Tao, W., & Zhang, L.
- Affiliations
- Jiangsu Hengrui Medicine (China) (CN)
- China Pharmaceutical University (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Li, Xin
- Wan, Hong
- Venue
- European Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 110
- Pages
- 51-61
- ISSN
- 0928-0987 (ISSN-L)
- OpenAlex
- W2577651608
- Cited by
- 227
- References
- 41
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 26 · 2023: 44 · 2022: 33 · 2021: 38 · 2020: 32 · 2019: 12 · 2018: 6
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmaceutical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National New Drug Key Program (2013ZX09102105)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- pyrotinib, irreversible tyrosine kinase inhibitor, HER2-positive breast cancer, structure-activity relationship, pharmacokinetics, drug-drug interactions, drug metabolism, metabolite toxicity, xenograft models, drug safety, clinical trials
- MeSH terms
- Acrylamides, Aminoquinolines, Animals, Antineoplastic Agents, Breast Neoplasms, Female, Humans, Structure-Activity Relationship, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Cell Line, Tumor, Rats, Metabolic Networks and Pathways, Heterografts, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
