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Purity: ≥98%
Debio 0932 (also known as CUDC-305) is a novel, potent and orally bioactive HSP90 (heat shock protein 90) inhibitor with IC50s of 100 and 103 nM for HSP90α and HSP90β, respectively. HSP90 that has been isolated from erlotinib-resistant NSCLC cells binds CUDC-305 firmly (IC50 70 nmol/L). This outcome is in good agreement with the strong antiproliferative activity in erlotinib-resistant non-small cell lung cancer cell lines (IC50 120-700 nmol/L) that has been previously documented. Additionally, it shows long-lasting inhibition of several oncoproteins and induces apoptosis in NSCLC cells resistant to erlotinib. Under subcutaneous xenograft models of H1975 and A549, which carry EGFR T790M mutations or K-ras mutations resulting in acquired and primary erlotinib resistance, respectively, CUDC-305 potently inhibits tumor growth. Moreover, CUDC-305 considerably increases animal survival in orthotopic lung tumor models of H1975 and A549; this effect may be partly explained by the compound's preferred exposure in lung tissue. Moreover, in an H1975 brain metastatic model, CUDC-305 can prolong animal survival, providing additional evidence of its blood-brain barrier-crossing capacity. CUDC-305 causes apoptosis in vivo while concurrently inducing the degradation of receptor tyrosine kinases and downstream signaling molecules of the PI3K/AKT and RAF/MEK/ERK pathways, which is consistent with its effects in different tumor models. In the H1975 tumor model, CUDC-305 improved the antitumor activity of a standard-of-care medication in a combination study. These findings imply that CUDC-305 may be useful in the management of NSCLC patients who have developed either primary or secondary resistance to EGFR inhibitor therapy.
| Targets |
HSP90α ( IC50 = 100 nM ); HSP90β ( IC50 = 103 nM )
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| ln Vitro |
Debio 0932 is an oral HSP90 inhibitor that has IC50 values of 103 nM for HSP90β and 100 nM for HSP90α, respectively. With a mean IC50 of 48.8 nM, Debio 0932 (CUDC-305) binds to the tumor HSP90 complex. In cancer cell lines, Debio 0932 (1 μM) stimulates the degradation of several HSP90 client proteins. Additionally, Debio 0932 exhibits inhibitory activities against 40 cancer cell lines (mean IC50, 220 nM) with an IC50 ranging from 40 to 900 nM (containing 34 solid and 6 hematologic tumor-derived lines)[1]. The HSP90 complex derived from cancer is strongly bound by Debio 0932, with an IC50 of 61.2 nM in H1975 cells and 74.2 nM in H1993 cells, respectively. In NSCLC cell lines harboring mutations that may confer resistance to erlotinib, Debio 0932 (CUDC-305, 1 μM) persistently induces oncoprotein degradation[3].
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| ln Vivo |
Debio 0932 (CUDC-305, 30 mg/kg, p.o.) shows good pharmacokinetic profiles in tumor-bearing nude mice. In several animal models of U87MG glioblastoma, Debio 0932 (160 mg/kg, p.o.) degrades HSP90 client proteins, inhibits tumor growth, and also increases survival time. By administering Debio 0932 at intervals of every other day (q2d), it also inhibits tumor growth in the U87MG s.c. tumor model in a dose-dependent manner[1]. By day 11, Debio 0932 (80 mg/kg, p.o.) considerably reduces psoriasis and lowers epidermal thickness in a model of psoriasis xenograft transplantation[2]. Additionally, Debio 0932 (CUDC-305) can pass through the blood-brain barrier. In the H1975 subcutaneous tumor model, Debio 0932 (80, 120, and 160 mg/kg, p.o.) inhibits tumor growth in a dose-dependent manner. In the erlotinib-resistant H1975 subcutaneous tumor model, Debio 0932 (160 mg/kg, p.o.) also enhances antitumor activity[3].
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| Cell Assay |
In 96-well plates, human cancer cell lines are plated with culture medium at a density of 5,000 to 10,000 per well. After that, the cells are incubated for 120 hours at different concentrations of the compounds (Debio 0932). Using the ATPlite kit, an ATP content assay is used to evaluate growth inhibition. To lyse cells and stabilize ATP, a 25-μL cell lysis solution is added to each well's 50-μL phenol red-free culture medium. After adding 25 microliters of substrate solutions to each well, the luminescence is measured using a TopCount liquid scintillation analyzer. The percentage of values obtained in untreated controls is used to express the values. Sigmoidal dose-response curve fitting is used with PRISM software to calculate IC50 values[1].
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| Animal Protocol |
Animals with appropriate tumor sizes are randomly assigned to different groups once their tumors have grown after implantation. Based on the body weight of the individual animal, Debio 0932 is administered orally in a 30% Captisol formulation. The same dosage paradigm is applied to the control group, which receives vehicle (30% Captisol). In combination studies, i.p. injections of 0.9% normal saline diluted with either paclitaxel or camptothecin-11 are administered twice a week[1].
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| References |
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| Additional Infomation |
Hsp90 Inhibitor Debio 0932 is an orally active and small molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Hsp90 inhibitor Debio 0932 specifically blocks Hsp90, thereby inhibiting its chaperone function and promoting the degradation of its client proteins, many of which are oncogenic signaling proteins involved in tumor cell proliferation and survival. This may lead to an inhibition of tumor cell proliferation. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stabilization and degradation of many oncogenic signaling proteins.
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| Molecular Formula |
C22H30N6O2S
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|---|---|
| Molecular Weight |
442.5776
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| Exact Mass |
442.215
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| Elemental Analysis |
C, 59.70; H, 6.83; N, 18.99; O, 7.23; S, 7.25
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| CAS # |
1061318-81-7
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| PubChem CID |
44156921
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
654.8±65.0 °C at 760 mmHg
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| Flash Point |
349.8±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.659
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| LogP |
4.32
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
31
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| Complexity |
591
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C1=C([H])C2=C(C([H])=C1N(C([H])([H])[H])C([H])([H])[H])OC([H])([H])O2)C1=NC2C(N([H])[H])=NC([H])=C([H])C=2N1C([H])([H])C([H])([H])N([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H]
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| InChi Key |
RVJIQAYFTOPTKK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H30N6O2S/c1-22(2,3)12-24-8-9-28-14-6-7-25-20(23)19(14)26-21(28)31-18-11-17-16(29-13-30-17)10-15(18)27(4)5/h6-7,10-11,24H,8-9,12-13H2,1-5H3,(H2,23,25)
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| Chemical Name |
2-[[6-(dimethylamino)-1,3-benzodioxol-5-yl]sulfanyl]-1-[2-(2,2-dimethylpropylamino)ethyl]imidazo[4,5-c]pyridin-4-amine
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| Synonyms |
CUDC305; CUDC-305; CUDC 305; Debio0932; Debio-0932; Debio 0932
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~75 mg/mL (~169.5 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.65 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.65 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.65 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2595 mL | 11.2974 mL | 22.5948 mL | |
| 5 mM | 0.4519 mL | 2.2595 mL | 4.5190 mL | |
| 10 mM | 0.2259 mL | 1.1297 mL | 2.2595 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 CUDC-305 binding affinity to HSP90 complex from NSCLC cell extracts.
A,pharmacodynamic study inK-ras–mutated A549 subcutaneous tumors.Mol Cancer Ther.2009 Dec;8(12):3296-306 |
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 A,schematic representation of the experimental design. A,efficacy study in the H1975 orthotopic lung tumor model compared with erlotinib (n= 10).Mol Cancer Ther.2009 Dec;8(12):3296-306 |
 A,CUDC-305 concentration-over-time curves in the lung, compared with other tissues following a single oral dose of CUDC-305 at 30 mg/kg.Mol Cancer Ther.2009 Dec;8(12):3296-306 |
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