ZINC69391
目录号 : GC66020
ZINC69391 是一种特异的 Rac1 抑制剂，通过在 Rac1 表面掩蔽 Trp56 残基来干扰 Rac1-GEF 的相互作用。ZINC69391 干扰 Rac1 与 Dock180 的相互作用，降低 Rac1-GTP水平。ZINC69391 诱导细胞凋亡，具有抗增殖和抗转移作用。
Cas No.:303094-67-9
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
ZINC69391, a specific Rac1 inhibitor, interferes with Rac1-GEF interaction by masking Trp56 residue on Rac1 surface. ZINC69391 interferes with the interaction of Rac1 with Dock180 and reduces Rac1-GTP levels. ZINC69391 induces apoptosis, and shows antiproliferative and antimetastatic effects[1][2][3].
ZINC69391 inhibits growth of U937, HL-60, KG1A and Jurkat cells with IC50s ranging from 41 to 54 μM[1].
ZINC69391 (50-100 μM; 24 hours) augments the enzymatic activity of caspase 3 in a concentration dependent manner[1].
ZINC69391 (0-125 μM; 72h) reduces cell proliferation of human glioma cells[2].
ZINC69391 (50-100 μM; 48 hours) triggers cell cycle arrest[2].
ZINC69391 (50 μM; 24 hours) triggers apoptosis on human acute leukemic cells[1].
Cell Proliferation Assay[2]
| Cell Line: | U-87 MG, LN229 cells |
| Concentration: | 0-125μM |
| Incubation Time: | 72 hours |
| Result: | Reduced cell proliferation in a concentration-dependent manner. |
Cell Cycle Analysis[2]
| Cell Line: | LN229 cells |
| Concentration: | 50, 100 μM |
| Incubation Time: | 48 hours |
| Result: | Resulted in a significant increased percentage of cells in the sub-G0/G1 phase in a concentration dependent manner. |
Apoptosis Analysis[1]
| Cell Line: | HL-60, U937 and KG1A cell lines |
| Concentration: | 50 μM |
| Incubation Time: | 24 hours |
| Result: | Led to a significant increase in apoptotic cells. |
ZINC69391 (25 mg/kg; i.p; daily for 21 days) impairs metastatic lung colonization in a syngeneic animal model[3].
| Animal Model: | Specific pathogen-free female BALB/c inbred mice (bearing F3II cells)[3] |
| Dosage: | 25 mg/kg body weight |
| Administration: | I.p; daily for 21 days |
| Result: | Significantly reduced by about 60% the formation of total metastatic lung colonies. |
| Cas No. | 303094-67-9 | SDF | Download SDF |
| 分子式 | C14H14F3N5 | 分子量 | 309.29 |
| 溶解度 | DMSO : 25 mg/mL (80.83 mM; ultrasonic and warming and heat to 60°C) | 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 | 3.2332 mL | 16.1661 mL | 32.3321 mL |
| 5 mM | 0.6466 mL | 3.2332 mL | 6.4664 mL |
| 10 mM | 0.3233 mL | 1.6166 mL | 3.2332 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。
NPM1-Mutated Patient-Derived AML Cells Are More Vulnerable to Rac1 Inhibition
Biomedicines 2022 Aug 4;10(8):1881.PMID:36009428DOI:10.3390/biomedicines10081881.
The prognosis of acute myeloid leukemia (AML) is poor, especially for the elderly population. Targeted therapy with small molecules may be a potential strategy to overcome chemoresistance and improve survival in AML. We investigated the inhibition of the signaling molecule ras-related C3 botulinum toxin substrate 1 (Rac1) in leukemia cells derived from 79 consecutive AML patients, using five Rac1 inhibitors: ZINC69391, ITX3, EHOP-016, 1A-116, and NSC23766. In vitro cell proliferation and apoptosis assays and the assessment of cytokine profiles in culture media were conducted. All five inhibitors had an antiproliferative effect; IC50 ranged from 3−24 µM. They induced significant apoptosis and necrosis compared to the untreated controls (p < 0.0001) at concentrations around IC40 and IC80. A high versus an intermediate or low antiproliferative effect was more common in NPM1-mutated (p = 0.002) and CD34-negative (p = 0.008) samples, and when NPM1 and FLT3 (p = 0.027) were combined. Presence of NPM1 mutation was associated with reduced viability after treatment with EHOP-016 (p = 0.014), ITX3 (p = 0.047), and NSC23766 (p = 0.003). Several cytokines crucial for leukemogenesis were reduced after culture, with the strongest effects observed for 1A-116 and NSC23766. Our findings suggest potent effects of Rac1 inhibition in primary AML cells and, interestingly, samples harboring NPM1 mutation seem more vulnerable.
Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells
Onco Targets Ther 2014 Oct 30;7:2021-33.PMID:25378937DOI:10.2147/OTT.S67998.
Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180-Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models.
Pharmacological Rac1 inhibitors with selective apoptotic activity in human acute leukemic cell lines
Oncotarget 2017 Oct 4;8(58):98509-98523.PMID:29228706DOI:10.18632/oncotarget.21533.
Rac1 GTPase has long been recognized as a critical regulatory protein in different cellular and molecular processes involved in cancer progression, including acute myeloid leukemia. Here we show the antitumoral activity of ZINC69391 and 1A-116, two chemically-related Rac1 pharmacological inhibitors, on a panel of four leukemic cell lines representing different levels of maturation. Importantly, we show that the main mechanism involved in the antitumoral effect triggered by the Rac1 inhibitors comprises the induction of the mitochondrial or intrinsic apoptotic pathway. Interestingly, Rac1 inhibition selectively induced apoptosis on patient-derived leukemia cells but not on normal mononuclear cells. These results show the potential therapeutic benefits of targeting Rac1 pathway in hematopoietic malignancies.
Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines
Anticancer Agents Med Chem 2014;14(6):840-51.PMID:24066799DOI:10.2174/18715206113136660334.
Rho GTPases play a key role in the regulation of multiple essential cellular processes, including actin dynamics, gene transcription and cell cycle progression. Aberrant activation of Rac1, a member of Rho family of small GTPases, is associated with tumorigenesis, cancer progression, invasion and metastasis. Particularly, Rac1 is overexpressed and hyperactivated in highly aggressive breast cancer. Thus, Rac1 appears to be a promising and relevant target for the development of novel anticancer drugs. We identified the novel Rac1 inhibitor ZINC69391 through a docking-based virtual library screening targeting Rac1 activation by GEFs. This compound was able to block Rac1 interaction with its GEF Tiam1, prevented EGF-induced Rac1 activation and inhibited cell proliferation, cell migration and cell cycle progression in highly aggressive breast cancer cell lines. Moreover, ZINC69391 showed an in vivo antimetastatic effect in a syngeneic animal model. We further developed the novel analog 1A-116 by rational design and showed to be specific and more potent than the parental compound in vitro and interfered Rac1-P-Rex1 interaction. We also showed an enhanced in vivo potency of 1A-116 analog. These results show that we have developed novel Rac1 inhibitors that may be used as a novel anticancer therapy.