Sulfatinib (HMPL-012)
(Synonyms: 5-羟基-2-甲基吲哚,HMPL-012) 目录号 : GC32805
A multi-kinase inhibitor
Cas No.:1308672-74-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | The KDR kinase inhibition activity is tested using the the Z-lyte assay kit. The testing system contains 300 ng/mL of recombinant human KDR catalytic domain, 10 μM of ATP, 1 μM of substrate peptide, and a test compound (Sulfatinib) at a series of different concentrations in 384-well plate; total volume is 10 μL. The enzyme inhibition proceeds at room temperature (25°C), for 1 hour at room temperature on the shaker. 5 μL of stop solution is added to stop the reaction[2]. |
Animal experiment: | The phamacokinetics of Sulfatinib are studied with male ICR mice (n=6 for each group, weight 20-30g) after a single intraveneous and oral dosing at 2.5 and 10mg/kg, respectively. For i.v. dosing formulation, Sulfatinib is dissolved in DMSO (0.25%)-solutol(10%)-ethanol(10%)-physiological saline(79.75%) at the concentration of 0.25 mg/mL. And the p.o. Dosing formulation (1mg/mL) is prepared with 0.5% CMC-Na. After i.v. Or p.o. Dosing, blood samples are collected via the ophthalmic vein at 0 (pre-close), 5, 15, 30 min and 1, 1.5, 2, 4, 8, 24 h, anti-coagulated with heparin-Na. After centrifugation, plasma samples are seprated and protein precipitated with acetonitrilel containing internal standard[2]. |
References: [1]. PCT Int. Appl. (2011), WO 2011060746 A1 20110526. | |
Sulfatinib is a multi-kinase inhibitor.1 It inhibits the receptor tyrosine kinases VEGFR1, VEGFR2, VEGFR3, FGFR1, colony stimulating factor 1 receptor (CSF1R), tropomyosin-related kinase B (TrkB), and FMS-related tyrosine kinase 3 (FLT3; IC50s = 2, 24, 1, 15, 4, 41, and 67 nM, respectively). It is selective for these kinases over a panel of 278 kinases (IC50s = >150 nM for all).
1.Qi, C., and Xu, J.Method of treating solid tumorsWO2018090324A1(2018)
| Cas No. | 1308672-74-3 | SDF | |
| 别名 | 5-羟基-2-甲基吲哚,HMPL-012 | ||
| Canonical SMILES | O=S(CC1=CC=CC(NC2=NC=CC(OC3=CC4=C(NC(C)=C4)C=C3)=N2)=C1)(NCCN(C)C)=O | ||
| 分子式 | C24H28N6O3S | 分子量 | 480.58 |
| 溶解度 | DMSO : ≥ 30 mg/mL (62.42 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 | 2.0808 mL | 10.4041 mL | 20.8082 mL |
| 5 mM | 0.4162 mL | 2.0808 mL | 4.1616 mL |
| 10 mM | 0.2081 mL | 1.0404 mL | 2.0808 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。
Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study
Lancet Oncol 2020 Nov;21(11):1500-1512.PMID:32966811DOI:10.1016/S1470-2045(20)30496-4.
Background: Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, Sulfatinib) in patients with extrapancreatic NETs. Methods: SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing. Findings: Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1-16·7) in the surufatinib group and 16·6 months (9·2-not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4-11·1) in the surufatinib group versus 3·8 months (3·7-5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22-0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure). Interpretation: Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population. Funding: Hutchison MediPharma.
Current treatments and future potential of surufatinib in neuroendocrine tumors (NETs)
Ther Adv Med Oncol 2021 Aug 31;13:17588359211042689.PMID:34484432DOI:10.1177/17588359211042689.
Neuroendocrine tumors (NETs) are rare, heterogeneous, often indolent tumors that predominantly originate in the lungs and gastrointestinal tract. An understanding of the biology and tumor microenvironment of NETs has led to the development of molecularly targeted treatment options including somatostatin analogs, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors and peptide receptor radionuclide therapy. Although increases in progression-free survival have been demonstrated, most currently approved NET therapies are limited by the development of tumor resistance. Surufatinib (HMPL-012, previously known as Sulfatinib) is a new, oral, small-molecule tyrosine kinase inhibitor that potently inhibits vascular endothelial growth-factor receptor 1-3, fibroblast growth-factor receptor 1, and colony-stimulating-factor-1 receptor. This unique combination of molecular activities inhibits tumor angiogenesis, regulates tumor-immune evasion, and may decrease tumor resistance. Surufatinib demonstrated statistically significant, clinically meaningful antitumor activity, including tumor shrinkage, in two phase III studies recently completed in China in advanced pancreatic NETs and advanced extrapancreatic NETs. The safety profile of surufatinib in neuroendocrine tumors studies was consistent with previous surufatinib clinical studies. In an ongoing study in United States (US) patients with NETs of pancreatic origin and NETs of extrapancreatic origin previously treated with everolimus or sunitinib, surufatinib has also demonstrated promising efficacy. Furthermore, the pharmacokinetic and safety profile of surufatinib in US patients is similar to data collected in studies done in China. These positive phase III results support the efficacy of surufatinib in patients with advanced, progressive, well-differentiated NETs regardless of tumor origin.
Surufatinib for the treatment of advanced extrapancreatic neuroendocrine tumors
Expert Rev Anticancer Ther 2021 Sep;21(9):917-926.PMID:34142932DOI:10.1080/14737140.2021.1944110.
Introduction: Surufatinib (also known as HMPL-012, Sulfatinib) is a novel oral tyrosine kinase inhibitor (TKI), which has the dual activity of anti-angiogenesis and immune regulation. In December 2020, surufatinib was approved as a monotherapy for unresectable locally advanced or metastatic, progressive nonfunctioning, well differentiated (grade 1 or 2) extrapancreatic neuroendocrine tumors (epNETs) in China.Areas covered: In this paper, the chemical properties, mechanism of action, pharmacokinetics, clinical efficacy, safety, and tolerability of surufatinib for treatment of advanced extrapancreatic NETs are introduced in detail. We performed a systematic review of the literature in PubMed and the following keywords were used: 'surufatinib,' 'Sulfatinib' and 'HMPL-012.'Expert opinion: Surufatinib is a potent, selective, and small-molecule TKI that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor 1 (FGFR1) and colony stimulating factor 1 receptor (CSF1R). Surufatinib showed an acceptable safety profile and encouraging antitumor activity in patients with advanced epNETs. The most frequently observed adverse events (AEs) were hypertension and proteinuria. Surufatinib provides a new treatment option for patients with advanced epNETs. More clinical trials of surufatinib are ongoing to develop a combination of therapy strategies and new indications for malignancies.
Surufatinib in Advanced Well-Differentiated Neuroendocrine Tumors: A Multicenter, Single-Arm, Open-Label, Phase Ib/II Trial
Clin Cancer Res 2019 Jun 15;25(12):3486-3494.PMID:30833272DOI:10.1158/1078-0432.CCR-18-2994.
Purpose: No antiangiogenic treatment is yet approved for extrapancreatic neuroendocrine tumors (NET). Surufatinib (HMPL-012, previously named Sulfatinib) is a small-molecule inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptor 1 and colony-stimulating factor 1 receptor. We conducted a single-arm phase Ib/II study of surufatinib in advanced NETs. Patients and methods: Patients with histologically well-differentiated, low or intermittent grade, inoperable or metastatic NETs were enrolled into a pancreatic or extrapancreatic NET cohort. Patients were treated with surufatinib 300 mg orally, once daily. The primary endpoints were safety and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (version 1.1). Results: Of the 81 patients enrolled, 42 had pancreatic NETs and 39 had extrapancreatic NETs. Most patients had radiologic progression within 1 year prior to enrollment (32 patients in each cohort). In the pancreatic and extrapancreatic NET cohorts, ORRs were 19% [95% confidence intervals (CI), 9-34] and 15% (95% CI, 6-31), disease control rates were 91% (95% CI, 77-97) and 92% (95% CI, 79-98), and median progression-free survival was 21.2 months (95% CI, 15.9-24.8) and 13.4 months (95% CI, 7.6-19.3), respectively. The most common grade ≥3 treatment-related adverse events were hypertension (33%), proteinuria (12%), hyperuricemia (10%), hypertriglyceridemia, and diarrhea (6% for each), and increased alanine aminotransferase (5%). Conclusions: Surufatinib showed encouraging antitumor activity and manageable toxicities in patients with advanced NETs. Two ongoing phase III studies, validating the efficacy of surufatinib in patients with NETs, will contribute to the clinical evidence.