Pz-1
目录号 : GC37047
Pz-1是有效地 RET 和 VEGFR2 受体酪氨酸激酶抑制剂，Pz-1抑制这两个野生型激酶的 IC50 值小于 1 nM。
Cas No.:1800505-64-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Pz-1 is a potent RET and VEGFR2 inhibitor with IC50s of less than 1 nM for both wild type kinases. IC50: < 1 nM (RET and VEGFR2)[1]
Pz-1 is a Type-II tyrosine kinase inhibitor, able to bind the DFG-out conformation of the kinase. In cell-based assays, 1.0 nM of Pz-1 strongly inhibits tyrosine phosphorylation of VEGFR2 and clinically relevant RET mutants, including those refractory to vandetanib and cabozantinib (RETV804M and RETV804L)[1].
Pz-1 is shown active on VEGFR2, which can block blood supply required for RET-stimulated growth. At 1.0 mg/kg/day per os, Pz-1 abrogates formation of tumors induced by RET-mutant fibroblasts and blocks phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 features no detectable toxicity up to 100.0 mg/kg, which indicates a large therapeutic window[1].
[1]. Frett B, et al. Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology. Angew Chem Int Ed Engl. 2015 Jul 20;54(30):8717-21.
| Cas No. | 1800505-64-9 | SDF | |
| Canonical SMILES | O=C(NC1=NOC(C(C)(C)C)=C1)CC2=CC=C(N3C4=CC=C(C5=CN(C)N=C5)C=C4N=C3)C=C2 | ||
| 分子式 | C26H26N6O2 | 分子量 | 454.52 |
| 溶解度 | Soluble in DMSO | 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 | 2.2001 mL | 11.0006 mL | 22.0012 mL |
| 5 mM | 0.44 mL | 2.2001 mL | 4.4002 mL |
| 10 mM | 0.22 mL | 1.1001 mL | 2.2001 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。
Characteristics of Bacillus sp. Pz-1 and its biosorption to Pb(II)
Ecotoxicol Environ Saf 2015 Jul;117:141-8.PMID:25855213DOI:10.1016/j.ecoenv.2015.03.033.
During the long and cold winter season in northern area of China, wastewater treatment is often inefficient which causes the substandard discharge. In this study, a lead-resistant psychrotrophilic bacterium was isolated and used as an adsorbent to remove Pb(II) from aqueous solution at 15 °C. The strain was identified and designated as Bacillus sp. Pz-1 based on the morphology, physiological-biochemical experiments and 16S rDNA sequence analysis. The minimal inhibitory concentration and antibiotic experiments revealed that Pz-1 had high resistance to 1500 mg L(-1) of Zn(II), 800 mg L(-1) of Cu(II), 400 mg L(-1) of Ni(II), 15 µg mL(-1) of chloramphenicol and 50 µg mL(-1) of streptomycin, but susceptibility to 200 mg L(-1) of Co(II). Scanning electron microscopy, energy dispersive X-ray spectroscopy and atomic force microscopy analyses showed that biosorption of Bacillus sp. Pz-1 to Pb(II) involved surface adsorption, ion exchange and micro-precipitate. Fourier transform infrared spectroscopy analyses indicated that hydroxyl, carbonyl and carboxyl on cells may play vital roles in Pb(II) adsorption. Besides, siderophore secreted by Pz-1 had beneficial impacts on the Pb(II) removal. Biosorption experiments were carried out as a function of initial Pb(II) concentration (50-500 mg L(-1)), pH (3.0-7.0), biomass concentration (5-50 g L(-1)) and contact time (5-40 min). Biosorption rate of 93.01% with adsorption capacity of 9.30 mg g(-1) was obtained under the initial Pb(II) concentration of 400 mg (-1), pH of 5.0, contact time of 20 min, biomass concentration of 40 g L(-1) and the temperature of 15 °C. The equilibrium data were well fitted with Langmuir model, which indicated the adsorption process of Pb(II) is monolayer adsorption. Bacillus sp. Pz-1 appeared to be an efficient biosorbent for removing Pb(II) from wastewater at low temperature.
Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases
Sci Rep 2021 Aug 9;11(1):16103.PMID:34373541DOI:10.1038/s41598-021-95612-4.
We have recently described Pz-1, a benzimidazole-based type-2 RET and VEGFR2 inhibitor. Based on a kinome scan, here we show that Pz-1 is also a potent (IC50 < 1 nM) TRKA/B/C inhibitor. Pz-1 potently inhibited proliferation of human cancer cells carrying either RET- or TRKA oncoproteins (IC50 ~ 1 nM), with a negligible effect against RET- and TRKA-negative cells. By testing mutations, known to mediate resistance to other compounds, RET G810R/S, but not L730I/V, E732K, V738A and Y806N, showed some degree of resistance to Pz-1. In the case of TRKA, G595R and F589L, but not G667C, showed some degree of resistance. In xenograft models, orally administered Pz-1 almost completely inhibited RET- and TRKA-mutant tumours at 1-3 mg/kg/day but showed a reduced effect on RET/TRKA-negative cancer models. The activity, albeit reduced, on RET/TRKA-negative tumours may be justified by VEGFR2 inhibition. Tumours induced by NIH3T3 cells transfected by RET G810R and TRKA G595R featured resistance to Pz-1, demonstrating that RET or TRKA inhibition is critical for its anti-tumourigenic effect. In conclusion, Pz-1 represents a new powerful kinase inhibitor with distinct activity towards cancers induced by oncogenic RET and TRKA variants, including some mutants displaying resistance to other drugs.
Optimization of Siderophore Production by Bacillus sp. Pz-1 and Its Potential Enhancement of Phytoextration of Pb from Soil
J Microbiol Biotechnol 2017 Aug 28;27(8):1500-1512.PMID:28633518DOI:10.4014/jmb.1705.05021.
In this study, the siderophore-producing characteristics and conditions of Bacillus sp. Pz-1 were investigated and the enhancement of siderophores on Pb uptake and translocation in Brassica juncea were determined. Results of single factor experiment showed that glucose, pH, and Pb(NO3)2 could stimulate Pz-1 growth and siderophore production. The maximum siderophore production of 90.52% siderophore units was obtained by response surface methodology optimization at the glucose concentration of 21.84 g/l, pH 6.18, and Pb(NO3)2 concentration of 245.04 μmol/l. The type of siderophore was hydroxamate and its concentration in the fermentation broth amounted to 32.24 μg/ml. Results of pot experiments indicated that the siderophores enhanced B. juncea to assimilate more Pb from soil with the uptake ratio from 1.04 to 2.74, and to translocate more Pb from underground to overground with the TF values from 1.21 to 1.48. The results revealed that Bacillus sp. Pz-1 could produce abundant siderophores and might be potentially used to augment the phytoextraction of Pb from soil.
Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology
Angew Chem Int Ed Engl 2015 Jul 20;54(30):8717-21.PMID:26126987DOI:10.1002/anie.201501104.
Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment-based chemical screen led to the identification of a novel RET inhibitor, Pz-1. Modeling and kinetic analysis identified Pz-1 as a type II tyrosine kinase inhibitor that is able to bind the "DFG-out" conformation of the kinase. Importantly, from a single-agent polypharmacology standpoint, Pz-1 was shown to be active on VEGFR2, which can block the blood supply required for RET-stimulated growth. In cell-based assays, 1.0 nM of Pz-1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg kg(-1) day(-1) per os, Pz-1 abrogated the formation of tumors induced by RET-mutant fibroblasts and blocked the phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 featured no detectable toxicity at concentrations of up to 100.0 mg kg(-1), which indicates a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry/polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways.
Bioisosteric Discovery of NPA101.3, a Second-Generation RET/VEGFR2 Inhibitor Optimized for Single-Agent Polypharmacology
J Med Chem 2020 May 14;63(9):4506-4516.PMID:32298114DOI:10.1021/acs.jmedchem.9b01336.
RET receptor tyrosine kinase is a driver oncogene in human cancer. We recently identified the clinical drug candidate Pz-1, which targets RET and VEGFR2. A key in vivo metabolite of Pz-1 is its less active demethylated pyrazole analogue. Using bioisosteric substitution methods, here, we report the identification of NPA101.3, lacking the structural liability for demethylation. NPA101.3 showed a selective inhibitory profile and an inhibitory concentration 50 (IC50) of <0.003 μM for both RET and VEGFR2. NPA101.3 inhibited phosphorylation of all tested RET oncoproteins as well as VEGFR2 and proliferation of cells transformed by RET. Oral administration of NPA101.3 (10 mg/kg/day) completely prevented formation of tumors induced by RET/C634Y-transformed cells, while it weakened, but did not abrogate, formation of tumors induced by a control oncogene (HRAS/G12V). The balanced synchronous inhibition of both RET and VEGFR2, as well the resistance to demethylation, renders NPA101.3 a potential clinical candidate for RET-driven cancers.