CUDC-101

Catalog No.S1194

CUDC-101 is a potent multi-targeted inhibitor against HDAC, EGFR and HER2 with IC50 of 4.4 nM, 2.4 nM, and 15.7 nM, and inhibits class I/II HDACs, but not class III, Sir-type HDACs. Phase 1.

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CUDC-101 Chemical Structure

CUDC-101 Chemical Structure
Molecular Weight: 434.49

Validation & Quality Control

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Product Description

Biological Activity

Description CUDC-101 is a potent multi-targeted inhibitor against HDAC, EGFR and HER2 with IC50 of 4.4 nM, 2.4 nM, and 15.7 nM, and inhibits class I/II HDACs, but not class III, Sir-type HDACs. Phase 1.
Targets EGFR [1] HDAC [1] HDAC1 [1] HDAC6 [1]

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IC50 2.4 nM 4.4 nM 4.5 nM 5.1 nM
In vitro Specific for class I and class II HDACs, CUDC-101 does not inhibit class III Sir-type HDACs. CUDC-101 displays weak activity against other protein kinases including KDR/VEGFR2, Lyn, Lck, Abl-1, FGFR-2, Flt-3, and Ret with IC50 of 0.85 μM, 0.84 μM, 5.91 μM, 2.89 μM, 3.43 μM, 1.5 μM, abd 3.2 μM, respectively. CUDC-101 displays broad antiproliferative activity in many human cancer cell types with IC50 of 0.04-0.80 μM, exhibiting a higher potency than erlotinib, lapatinib, and combinations of vorinostat with either erlotinib or lapatinib in most cases. CUDC-101 potently inhibits lapatinib- and erlotinib-resistant cancer cell lines. [1] CUDC-101 inhibits the erlotinib-resistant EGFR mutant T790M although its effects are incomplete with an Amax of ~60% of peak enzyme activity after inhibition. CUDC-101 treatment increases the acetylation of histone H3 and H4, as well as the acetylation of non-histone substrates of HDAC such as p53 and α-tubulin, in a dose-dependant manner in various cancer cell lines. CUDC-101 also suppresses HER3 expression, Met amplification, and AKT reactivation in tumor cells. [2]
In vivo Administration of CUDC-101 at 120 mg/kg/day induces tumor regression in the Hep-G2 liver cancer model, which is more efficacious than that of erlotinib at its maximum tolerated dose (25 mg/kg/day) and vorinostat at an equimolar concentration dose (72 mg/kg/day). CUDC-101 inhibits the growth of erlotinib-sensitive H358 NSCLC xenografts in a dose-dependent manner. CUDC-101 also shows potent inhibition of tumor growth in the erlotinib-resistant A549 NSCLC xenograft model. CUDC-101 produces significant tumor regression in the lapatinib-resistant, HER2-negative, EGFR-overexpressing MDA-MB-468 breast cancer model and the EGFR-overexpressing CAL-27 head and neck squamous cell carcinoma (HNSCC) model. Additionally, CUDC-101 inhibits tumor growth in the K-ras mutant HCT116 colorectal and EGFR/HER2 (neu)-expressing HPAC pancreatic cancer models. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

HDAC, EGFR and HER2 inhibition assays The activities of Class I and II HDACs are assessed using the Biomol Color de Lys system. Briefly, HeLa cell nuclear extracts are used as a source of HDACs. Different concentrations of CUDC-101 are added to HeLa cell nuclear extracts in the presence of a colorimetric artificial substrate. Developer is added at the end of the assay and enzyme activity is measured in the Wallac Victor II 1420 microplate reader at 405 nM. EGFR and HER2 kinase activity are measured using HTScan EGF receptor and HER2 kinase assay kits. Briefly, the GST-EGFR fusion protein is incubated with synthetic biotinylated peptide substrate and varying concentrations of CUDC-101 in the presence of 400 mM ATP. Phosphorylated substrate is captured with strapavidin-coated 96-well plates. The level of phosphorylation is monitored by antiphospho-tyrosine- and europium-labeled secondary antibodies. The enhancement solution is added at the end of the assay and enzyme activity is measured in the Wallac Victor II 1420 microplate reader at 615 nM.

Cell Assay: [1]

Cell lines HCC827, H358, H460, HepG2, Hep3B2, Sk-Hep-1, Capan1, BxPc3, MCF-7, MDA-MB-231, and Sk-Br-3
Concentrations Dissolved in DMSO, final concentrations ~10 μM
Incubation Time 72 hours
Method Cancer cell lines are plated at 5000 to 10000 cells per well in 96-well flatbottomed plates with varying concentrations of CUDC-101. The cells are incubated with CUDC-101 for 72 hours in the presence of 0.5% of fetal bovine serum. Growth inhibition is assessed by an adenosine triphosphate (ATP) content assay using the Perkin-Elmer ATPlite kit. Apoptosis is routinely assessed by measuring the activities of Caspase-3 and -7 using Apo-ONE Homogeneous Assay Kit.

Animal Study: [1]

Animal Models Female athymic mice (nude nu/nu CD-1) inoculated with Hep-G2, H358, A549, MDA-MB468, HCT116, CAL-27, HepG2, or HPAC
Formulation Formulated in 30% Captisol solution
Dosages ~120 mg/kg/day
Administration Administered via i.v.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Cai X, et al. J Med Chem, 2010, 53(5), 2000-2009.

[2] Lai CJ, et al. Cancer Res, 2010, 70(9), 3647-3656.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-05-29)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01702285 Terminated Cancer Curis, Inc. September 2012 Phase 1
NCT01384799 Completed Head and Neck Cancer Curis, Inc. November 2011 Phase 1
NCT01171924 Completed Head and Neck Cancer|Liver Cancer|Breast Cancer|Gastric Cancer|Non-Small Cell Lung Cancer Curis, Inc. July 2010 Phase 1
NCT00728793 Completed Tumors Curis, Inc. August 2008 Phase 1

Chemical Information

Download CUDC-101 SDF
Molecular Weight (MW) 434.49
Formula

C24H26N4O4

CAS No. 1012054-59-9
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 20 mg/mL (46.03 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 15% Captisol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide

Customer Product Validation (3)


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Rating
Source ACS Med Chem Lett 2013 4(9), 858-62. CUDC-101 purchased from Selleck
Method
Cell Lines MDA-MB-231 tumor bearing mice
Concentrations 20 mg/kg
Incubation Time 24 h
Results To test the HDAC specificity of [64Cu]7 in vivo, blocking experiments were performed by coinjection of 20 mg/kg nonradioactive HDAC inhibitor CUDC-101 with [64Cu]7 . The MDA-MB-231 tumor uptake values for blocking experiments were 0.48 ?0.24, 0.94 ?0.37, and 1.22 ?0.31% ID/g at 2, 6, and 24 h p.i., respectively, which showed significant decreasing compared with that of the imaging group at all time points.

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Rating
Source Dr. Zhang of Tianjin Medical University. CUDC-101 purchased from Selleck
Method Western blot
Cell Lines MDB-MA-231 cells
Concentrations 0.01-20 μM
Incubation Time 3 h
Results Increased Histone H3 acetylation in MDA-MB-231 cells treated with CUDC-101 was observed.

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Rating
Source Dr. Xiangbing Meng of University of Iowa. CUDC-101 purchased from Selleck
Method WST-1 method
Cell Lines Hec50 cell, lshikawa cells, SKOV3 cells, Caov cells, PA-1 cells
Concentrations 0-1200 nM
Incubation Time 3 d
Results CUDC-101 potently inhibited the survival of Hec50, lshikawa, SKOV3, Caov and PA-1 cells in a dose-dependent manner.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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