Pyrotinib (SHR-1258)
(Synonyms: 吡咯替尼; SHR-1258) 目录号 : GC32733
Pyrotinib (SHR-1258) (SHR-1258) 是一种有效的选择性 EGFR/HER2 双重抑制剂，IC50 分别为 13 和 38 nM。
Cas No.:1269662-73-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Cell experiment: |
Cancer cells (A431, SK-BR-3 and NCI-N87) are treated with a series of concentrations of Pyrotinib for 72 hours. Cell proliferation is determined by a sulforhodamine B (SRB) method. The IC50 values are calculated by the data of inhibition rates of serial concentrations of test compounds[1]. |
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Animal experiment: |
Rats: Test compounds (include Pyrotinib) are administrated in both intravenous (i.v.) and intragastric (i.g.) for mice to obtain their bioavailability. Plasma samples of nude mice is collected at pre-dose and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 h after the IV administration[1]. Mice: In vivo efficacy studies are performed on BALB/Ca-nude mice (6 to 7 weeks, female) from SLAC. Nude mice are hypodermic inoculated BT-474 human breast cancer cell or SK-OV-3 ovarian cancer cell. After tumor grows to 150-250 mm3, mice are randomly divided into groups and dosed with Pyrotinib (2.5, 5, 10, 20 mg/kg) once daily. The volume of tumors and the weight of the mice are measured and recorded for 2-3 times per week[1]. |
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References: [1]. Li X, et al. 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 Jan 21. pii: S0928-0987(17)30043-X. |
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Pyrotinib (SHR-1258) is a potent and selective EGFR/HER2 dual inhibitor with IC50s of 13 and 38 nM, respectively.
Pyrotinib has high potency in HER2-dependent cell lines (BT474, SK-OV-3), while showing much weaker inhibition in the HER2 negative cell line (MDA-MB-231). It inhibits BT474 and SK-OV-3Pyrotinib cells with IC50s of 5.1 and 43 nM, respectively. Pyrotinib displays high selectivity as HKI-272 when tested in a panel of different kinases such as KDR, c-Kit, PDGFRβ, c-Src and C-Met (c-Src with an IC50 of 790 nM, and others over 3000 nM)[1].
Pyrotinib has acceptable bioavailability of 20.6%, 43.5% and 13.5% in nude mice, rats and dogs, respectively. Pyrotinib has favorable drug-like physicochemical properties and shows relatively higher oral exposure in human subjects with a much longer half life than that of preclinical animal species such as mouse, rat and dog. The TGI % (tumor growth inhibition) of Pyrotinib on day 21 is 109%, 157%, 159% at the doses of 5 mg/kg, 10 mg/kg, 20 mg/kg respectively. Pyrotinib in SK-OV-3 ovarian xenograft model shows TGI% on day 21 of 2%, 12%, 83% at the doses of 2.5 mg/kg, 5 mg/kg, 10 mg/kg respectively), which further confirms its robust in vivo antitumor efficacy at 10 mg/kg[1].
[1]. Li X, et al. 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 Jan 21. pii: S0928-0987(17)30043-X.
| Cas No. | 1269662-73-8 | SDF | |
| 别名 | 吡咯替尼; SHR-1258 | ||
| Canonical SMILES | O=C(NC1=C(OCC)C=C2N=CC(C#N)=C(NC3=CC=C(OCC4=NC=CC=C4)C(Cl)=C3)C2=C1)/C=C/[C@@H]5N(C)CCC5 | ||
| 分子式 | C32H31ClN6O3 | 分子量 | 583.08 |
| 溶解度 | DMSO : 0.172 mg/mL (0.29 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.715 mL | 8.5752 mL | 17.1503 mL |
| 5 mM | 0.343 mL | 1.715 mL | 3.4301 mL |
| 10 mM | 0.1715 mL | 0.8575 mL | 1.715 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
HER2-targeted therapies in gastric cancer
Biochim Biophys Acta Rev Cancer 2021 Aug;1876(1):188549.PMID:33894300DOI:10.1016/j.bbcan.2021.188549.
Molecular targeted therapy of cancer has always been the focus of clinicians. Among those therapeutic targets, the human epidermal growth factor receptor-2 (HER-2) signaling pathway is one of the most popular targets for translational research in cancer. However, unlike prospect in breast cancer, HER-2 inhibitor trastuzumab is the only molecular targeted drug approved by US Food and Drug Administration (FDA) for the first-line treatment of HER-2 positive advanced gastric cancer. On this basis, a variety of novel HER2- targeted drugs for gastric cancer are under development, and related clinical researches are in full swing, including small molecular kinase inhibitors (e.g., afatinib, neratinib, Pyrotinib), antibody-drug conjugates (e.g., DS-8201a, RC48-ADC) and other novel therapies (e.g., ZW25, CAR-T, BVAC-B). In this study, we will summarize the recent advances in anti-HER-2 agents, potential mechanisms of resistance to HER2-targeted therapy in HER2-positive gastric cancer. We will also discuss the future prospects of potential strategies to overcome anti-HER-2 resistance and development of novel anti-HER-2 approaches for the treatment of HER2-positive gastric cancer patients.
Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial
Lancet Oncol 2021 Mar;22(3):351-360.PMID:33581774DOI:10.1016/S1470-2045(20)30702-6.
Background: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of Pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. Methods: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral Pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. Findings: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received Pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with Pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the Pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the Pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the Pyrotinib group and one sudden death in the lapatinib group was considered treatment related. Interpretation: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. Funding: Jiangsu Hengrui Medicine and National Key R&D Program of China. Translations: For the Chinese translation of the abstract see Supplementary Materials section.
Consensus for HER2 alterations testing in non-small-cell lung cancer
ESMO Open 2022 Feb;7(1):100395.PMID:35149428DOI:10.1016/j.esmoop.2022.100395.
Human epidermal growth factor receptor 2 (HER2) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity. Its alterations, including mutation, amplification and overexpression, could result in oncogenic potential and have been detected in many cancers such as non-small-cell lung cancer (NSCLC). Such alterations are, in general, considered markers of poor prognosis. Anti-HER2 antibody-drug conjugates, e.g. trastuzumab deruxtecan (T-DXd, DS-8201) and disitamab vedotin (RC48), were recently approved for HER2-positive breast and gastric cancers. Meanwhile, several HER2-targeted drugs, such as T-DXd, neratinib, afatinib, poziotinib and Pyrotinib, have been evaluated in patients with advanced NSCLC, with several of them demonstrating clinical benefit. Therefore, identifying HER2 alterations is pivotal for NSCLC patients to benefit from these targeted therapies. Recent guidelines on HER2 testing were developed for breast and gastric cancer, however, and have not been fully established for NSCLC. The expert group here reached a consensus on HER2 alteration testing in NSCLC with the focus on clinicopathologic characteristics, therapies, detection methods and diagnostic criteria for HER2-altered NSCLC patients. We hope this consensus could improve the clinical management of NSCLC patients with HER2 alterations.
HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now
NPJ Breast Cancer 2021 May 20;7(1):56.PMID:34016991DOI:10.1038/s41523-021-00265-1.
Human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20-25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and Pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.
Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial
Cell Res 2021 Feb;31(2):178-186.PMID:32719455DOI:10.1038/s41422-020-0375-9.
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) Pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1-8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%-41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%-75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%-48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.