MK-0429 (L-000845704)
(Synonyms: L-000845704) 目录号 : GC32055
MK-0429 (L-000845704) (L-000845704) 是一种具有口服活性的、有效的、选择性的非肽类泛整合素拮抗剂，对于 α 的 IC50 值为 1.6 nM、2.8 nM、0.1 nM、0.7 nM、0.5 nM 和 12.2 nM ;vβ1, αvβ3, αvβ5, αvβ6, αvβ8 and α5β1, respectively.
Cas No.:227963-15-7
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
MK-0429 is a potent integrin antagonist with IC50s of 12.2 nM (α5β1 integrin) and 2.8 nM (αvβ3 integrin), respectively.
[1]. Zhou X, et al. An integrin antagonist (MK-0429) decreases proteinuria and renal fibrosis in the ZSF1 rat diabetic nephropathy model.Pharmacol Res Perspect. 2017 Oct; 5 (5).
| Cas No. | 227963-15-7 | SDF | |
| 别名 | L-000845704 | ||
| Canonical SMILES | O=C1N([C@H](C2=CC=C(OC)N=C2)CC(O)=O)CCN1CCCC3=NC4=C(C=C3)CCCN4 | ||
| 分子式 | C23H29N5O4 | 分子量 | 439.51 |
| 溶解度 | DMSO : 250 mg/mL (568.82 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 | 2.2753 mL | 11.3763 mL | 22.7526 mL |
| 5 mM | 0.4551 mL | 2.2753 mL | 4.5505 mL |
| 10 mM | 0.2275 mL | 1.1376 mL | 2.2753 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。
Orally active αvβ3 integrin inhibitor MK-0429 reduces melanoma metastasis
Oncol Rep 2015 Jun;33(6):2737-45.PMID:25872534DOI:10.3892/or.2015.3910.
Melanoma remains one of the most aggressive types of cancer with a historically low survival rate. The αvβ3 integrin is involved in the progression of malignant melanoma. In the present study, the efficacy of MK-0429, a selective inhibitor of the αvβ3 integrin, was evaluated for its potential in the prevention of melanoma metastasis. Female B6D2F1 mice injected via the tail vein with murine B16F10 melanoma developed lung metastases within ~10 days. In the first experiment, the prevention of lung metastasis was assessed in the model treated with either vehicle, MK-0429 at 100 and 300 mg/kg orally twice daily or cyclophosphamide at 300 mg/kg, i.p. once daily. Study endpoints included determination of the study time period to achieve metastasis in lungs in this model, evaluation of the health effects on the study animals, the total number of lung colonies identified and lung tumor area. Unlike cyclophosphamide, the MK-0429 treatment did not lead to a significant weight reduction in mice. MK-0429 at 100 and 300 mg/kg reduced the number of metastatic tumor colonies by 64 and 57%, respectively, and the high dose also reduced the tumor area by 60% as compared to the vehicle. The second experiment employed B16F10 luciferase-expressing cells to examine the de novo progression of melanoma metastasis over 15 days with bioluminescent imaging of mice treated with MK-0429 at 300 mg/kg as compared to the vehicle. Tumor burden progressively advanced in the lungs of the B16F10-treated animals. However, MK-0429 reduced the progression of ventral and dorsal lung metastases by 22 and 38%, respectively, as compared to the vehicle, by study completion. Quantification of ex vivo tumor burden showed a 30-40% reduction in lung colonies by MK-0429. The two studies collectively demonstrated that MK-0429 was safe and efficacious in significantly decreasing melanoma metastasis in the lungs. The results emphasized the potential of MK-0429 as a novel, therapeutic agent for the prevention of metastatic melanoma.
Inhibition of angiogenesis and tumor progression of MK-0429, an integrin αvβ3 antagonist, on oral squamous cell carcinoma
J Cancer Res Clin Oncol 2022 Dec;148(12):3281-3292.PMID:35713706DOI:10.1007/s00432-022-04100-3.
Purpose: Integrin αvβ3 is an essential molecule for tumor angiogenesis. This study aimed to investigate the anti-tumor effect of MK-0429, an integrin αvβ3 antagonist, on oral squamous cell carcinoma (OSCC) through its inhibitory effect on angiogenesis. Methods: In this study, we investigated the effect of MK-0429 on cellular function and angiogenesis in vitro with the use of an immortalized human umbilical vein endothelial cell, HUEhT-1, which is immortalized by the electroporatic transfection of hTERT. The effect of MK-0429 on the integrin αvβ3 signaling pathway was examined by FAK, MEK1/2 and ERK 1/2 phosphorylation. The anti-angiogenic effect of MK-0429 was evaluated by in vitro tube formation assay. The anti-tumor effect on OSCC was assessed by administrating MK-0429 to mouse oral cancer xenografts. Results: MK-0429 inhibited cell proliferation, migration, and adhesion of HUEhT-1 in a dose-dependent manner. FAK, MEK and ERK phosphorylation were significantly blocked by MK-0429 treatment. Tube formation was suppressed by MK-0429 in dose-dependent manner. Tumor progression was significantly suppressed by MK-0429 administration in mouse oral cancer xenografts. Histological study revealed that MK-0429 decreased tumor vascularization. Conclusion: These results indicated integrin αvβ3 as a therapeutic target for OSCC and suggested that MK-0429 might be clinically applicable as an anti-tumor agent with potent anti-angiogenic activity.
An integrin antagonist (MK-0429) decreases proteinuria and renal fibrosis in the ZSF1 rat diabetic nephropathy model
Pharmacol Res Perspect 2017 Oct;5(5):e00354.PMID:28971604DOI:10.1002/prp2.354.
Multiple integrins have been implicated in modulating renal function. Modulation of integrin function can lead to pathophysiological processes associated with diabetic nephropathy such as alterations in the glomerular filtration barrier and kidney fibrosis. The complexity of these pathophysiological changes implies that multiple integrin subtypes might need to be targeted to ameliorate the progression of renal disease. To address this hypothesis, we investigated the effects of MK-0429, a compound that was originally developed as an αvβ3 inhibitor for the treatment of osteoporosis, on renal function and fibrosis. We demonstrated that MK-0429 is an equipotent pan-inhibitor of multiple av integrins. MK-0429 dose-dependently inhibited podocyte motility and also suppressed TGF-β-induced fibrosis marker gene expression in kidney fibroblasts. Moreover, in the obese ZSF1 rat model of diabetic nephropathy, chronic treatment with MK-0429 resulted in significant reduction in proteinuria, kidney fibrosis, and collagen accumulation. In summary, our results suggest that inhibition of multiple integrin subtypes might lead to meaningful impact on proteinuria and renal fibrosis in diabetic nephropathy.
Thermodynamic Understanding of an Aza-Michael Reaction Enables Five-Step Synthesis of the Potent Integrin Inhibitor MK-0429
J Org Chem 2021 Dec 3;86(23):17523-17527.PMID:34723526DOI:10.1021/acs.joc.1c02375.
We describe a general strategy for the aza-Michael addition of nucleophilic heterocycles into β-substituted acrylates using potassium tert-butoxide as catalyst. Demonstrating that the reaction is under thermodynamic control underpins optimization efforts and enables rapid exploration of the substrate scope, with yields ranging from 55% to 94%. We further leverage these lessons in a significantly shortened synthesis of MK-0429, a potent pan-integrin inhibitor previously taken into human clinical trials for the treatment of prostate cancer and osteoporosis.
Discovery of a new class of integrin antibodies for fibrosis
Sci Rep 2021 Jan 22;11(1):2118.PMID:33483531DOI:10.1038/s41598-021-81253-0.
Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of αv integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimab's yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple αv integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFβ activation. In IPF patient lung fibroblasts, TGFβ treatment induced profound αSMA expression in phenotypic imaging assays and Ab-31 demonstrated potent in vitro activity at inhibiting αSMA expression, suggesting that the integrin antibody is able to modulate TGFβ action though mechanisms beyond the inhibition of latent TGFβ activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases.