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1A-116 Sale

目录号 : GC32770

1A-116 is a Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer, such as breast cancer, prevents Rac1-regulated processes involved in the primary tumorigenesis and metastastic processes.

1A-116 Chemical Structure

Cas No.:1430208-73-3

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10mM (in 1mL DMSO)
¥1,386.00
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5mg
¥1,260.00
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10mg
¥2,070.00
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25mg
¥4,140.00
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50mg
¥6,660.00
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100mg
¥9,900.00
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment:

5×103 MCF7::pcDNA.3 and MCF7::C1199 cells are plated in 96-wells plates and 24 hours later are treated for 72 hours with different concentrations of 17-β-Estradiol to evaluate hormone response. To evaluate the reversion of 4-hydroxytamoxifen (Tam) resistance by 1A-116, MCF7::C1199 cells are treated with Tam (0.01 μM, 0.1 μM and 1 μM), 1A-116 (4 μM) or combination of both for 72 hours. Cell growth is measured by colorimetric crystal violet assay. The analysis of hormone-dependent growth and Tam resistance reversion is determined using PRISM 6, Version 6.01. Results shown correspond to the average of three independent experiments[1].

Animal experiment:

Specific pathogen-free female BALB/c inbred mice with an age of 8 to 10 weeks and an average weight of 20 g, are used. They are housed in plastic cages under standard conditions and have access to rodent chow and water ad libitum. On day 0, 2×105 viable F3II cells in 0.3 mL Dulbecco’s modified Eagle medium (DMEM) are injected into the lateral tail vein. Mice are injected i.p at daily doses of 3 mg/kg body weight 1A-116 or vehicle. Treatment is carried out from day 0 to day 21. On day 21 mice are sacrificed and lungs are excised and immediately fixed in Bouin’s solution. Superficial lung nodules are counted under dissection microscope[2].

References:

[1]. Gonzalez N, et al. Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells. Cell Signal. 2017 Jan;30:154-161.
[2]. Cardama GA, et al. 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.

产品描述

1A-116 is a Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer, such as breast cancer, prevents Rac1-regulated processes involved in the primary tumorigenesis and metastastic processes.

[1] Cardama GA, et al. Anticancer Agents Med Chem. 2014;14(6):840-51.

Chemical Properties

Cas No. 1430208-73-3 SDF
Canonical SMILES N=C(NC1=CC=CC=C1C(F)(F)F)NC2=CC(C)=CC(C)=C2
分子式 C16H16F3N3 分子量 307.31
溶解度 DMSO : 100 mg/mL (325.40 mM);Water : < 0.1 mg/mL (insoluble) 储存条件 Store at -20°C
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1 mM 3.254 mL 16.2702 mL 32.5404 mL
5 mM 0.6508 mL 3.254 mL 6.5081 mL
10 mM 0.3254 mL 1.627 mL 3.254 mL
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Research Update

Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma

Pharmaceutics 2021 Jul 16;13(7):1091.PMID:34371781DOI:10.3390/pharmaceutics13071091.

The Ras homologous family of small guanosine triphosphate-binding enzymes (GTPases) is critical for cell migration and proliferation. The novel drug 1A-116 blocks the interaction site of the Ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase with some of its guanine exchange factors (GEFs), such as T-cell lymphoma invasion and metastasis 1 (TIAM1), inhibiting cell motility and proliferation. Knowledge of circadian regulation of targets can improve chemotherapy in glioblastoma. Thus, circadian regulation in the efficacy of 1A-116 was studied in LN229 human glioblastoma cells and tumor-bearing nude mice. Methods: Wild-type LN229 and BMAL1-deficient (i.e., lacking a functional circadian clock) LN229E1 cells were assessed for rhythms in TIAM1, BMAL1, and period circadian protein homolog 1 (PER1), as well as Tiam1, Bmal1, and Rac1 mRNA levels. The effects of 1A-116 on proliferation, apoptosis, and migration were then assessed upon applying the drug at different circadian times. Finally, 1A-116 was administered to tumor-bearing mice at two different circadian times. Results: In LN229 cells, circadian oscillations were found for BMAL1, PER1, and TIAM1 (mRNA and protein), and for the effects of 1A-116 on proliferation, apoptosis, and migration, which were abolished in LN229E1 cells. Increased survival time was observed in tumor-bearing mice when treated with 1A-116 at the end of the light period (zeitgeber time 12, ZT12) compared either to animals treated at the beginning (ZT3) or with vehicle. Conclusions: These results unveil the circadian modulation in the efficacy of 1A-116, likely through RAC1 pathway rhythmicity, suggesting that a chronopharmacological approach is a feasible strategy to improve glioblastoma treatment.

Preclinical Efficacy and Toxicology Evaluation of RAC1 Inhibitor 1A-116 in Human Glioblastoma Models

Cancers (Basel) 2022 Sep 30;14(19):4810.PMID:36230732DOI:10.3390/cancers14194810.

Malignant gliomas are the most common primary central nervous system tumor in adults. Despite current therapeutics, these tumors are associated with poor prognosis and a median survival of 16 to 19 months. This highlights the need for innovative treatments for this incurable disease. Rac1 has long been associated with tumor progression and plays a key role in glioma's infiltrative and invasive nature. The aim of this study is to evaluate the 1A-116 molecule, a Rac1 inhibitor, as targeted therapy for this aggressive disease. We found that targeting Rac1 inhibits cell proliferation and cell cycle progression using different in vitro human glioblastoma models. Additionally, we evaluated 1A-116 in vivo, showing a favorable toxicological profile. Using in silico tools, 1A-116 is also predicted to penetrate the blood-brain barrier and present a favorable metabolic fate. In line with these results, 1A-116 i.p daily treatment resulted in a dose-dependent antitumor effect in an orthotopic IDH-wt glioma model. Altogether, our study provides a strong potential for clinical translation of 1A-116 as a signal transduction-based precision therapy for glioma and also increases the evidence of Rac1 as a key molecular target.

Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

Front Cell Dev Biol 2020 Apr 15;8:240.PMID:32351958DOI:10.3389/fcell.2020.00240.

In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A-116 is also able to inhibit the oncogenic Rac1P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development.

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.

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.