| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| 100mg | |||
| Other Sizes |
| Targets |
JQAD1 targets the histone acetyltransferase EP300 (p300) for degradation via the ubiquitin-proteasome pathway in a CRBN-dependent manner. EP300 is a transcriptional coactivator that acetylates histone and non-histone proteins, playing critical roles in gene expression, cell proliferation, and differentiation. JQAD1 selectively induces degradation of p300 over its paralog CBP in MYCN-amplified neuroblastoma cells at 10 µM for 24 hours. By degrading EP300, JQAD1 suppresses H3K27ac modification and downstream oncogenic gene expression.
|
|---|---|
| ln Vitro |
JQAD1 stimulates LAMP in head Kelly NB cells, suppresses H3K27ac modification, and inhibits the production of EP300, but not in CRBN knockout cells [1]. Treatment with JQAD1 (0.5 or 1 μM; 6-96 h) causes an early temporal activation of JQAD1 (1 μM; 12-36 h)-induced disinfection of Kelly NB cells [1]. Kelly and NGP cells were sterilized when exposed to JQAD1 (0.5 μM) for 24 hours, as evidenced by the enhancement of the sub-G1 peak in these cells [1]. JQAD1 inhibits MYCN expression at 0.5 and 1 μM for 24 hours [1]. JQAD1 inhibits MYCN expression at 0.5 and 1 μM for 24 hours [1]. Wide-ranging CRBN-dependent cross-module anti-tumor action is exhibited by JQAD1 (1.2 nM–20 μM; 5 days) [1]. There is a time-dependent induction of JQAD1. H3K27ac on chromatin is lost at μM; 24 h] [1].
In vitro, JQAD1 achieves a DC50 of ≤31.6 nM for EP300 degradation in neuroblastoma cell lines. It shows no significant effect on the paralogous coactivator CBP at concentrations that induce near-complete EP300 depletion. JQAD1 suppresses both H3K27ac and EP300 expression levels and induces apoptosis. In Kelly MYCN-amplified neuroblastoma cells, treatment with 10 µM JQAD1 for 24 hours selectively induces p300 degradation over CBP. The compound's effects are proteasome-dependent, confirming the PROTAC mechanism of action. |
| ln Vivo |
JQAD1 (40 mg/kg; ip; once daily for 21 days) inhibits tumor growth in Kelly NB xenografted NSG mice [1].
In vivo, JQAD1 suppresses tumor growth in NSG mice xenografted with Kelly cells. CRC and MYCN genes are downregulated in tumors treated with JQAD1. These data demonstrate that EP300 degradation by JQAD1 is sufficient to inhibit tumor growth in a neuroblastoma xenograft model. The compound's in vivo efficacy supports the therapeutic potential of EP300 degradation in MYCN-amplified cancers. Further studies would be needed to evaluate its efficacy in other cancer types. |
| Enzyme Assay |
For in vitro degradation assays, neuroblastoma cells (such as Kelly or other MYCN-amplified lines) are treated with JQAD1 at concentrations ranging from 0.001-10 µM for 4-24 hours. Cell lysates are prepared and subjected to SDS-PAGE followed by Western blotting with antibodies against EP300, CBP, H3K27ac, and loading controls (such as GAPDH or tubulin). Protein band intensities are quantified by densitometry, and DC50 values are calculated by fitting dose-response curves of remaining EP300 protein levels.
|
| Cell Assay |
Western Blot Analysis[1]
Cell Types: MYCN-amplified NB cells Tested Concentrations: 0.1, 0.5, 1, 3, 5, and 10 µM Incubation Duration: 24 h Experimental Results: Confirmed dose. EP300 degrades first at 16 hrs (hours)[1]. Dependent reduction in EP300 expression and parallel loss of H3K27ac modification. The selective loss of induced EP300 expression coincides with the cleavage of PARP1, signaling the onset of apoptosis. Western Blot Analysis[1] Cell Types: Kelly NB Cell Tested Concentrations: 1 µM Incubation Duration: 12, 24 and 36 hrs (hours) Experimental Results: Expression of cleaved caspase-3 and cleaved PARP1 increased in a dose-dependent manner. For cell viability and apoptosis assays, neuroblastoma cells are seeded in 96-well plates and treated with JQAD1 at various concentrations for 48-72 hours. Cell viability is measured using CellTiter-Glo or MTT assays. Apoptosis is assessed by staining with Annexin V-FITC and propidium iodide followed by flow cytometry analysis. Caspase-3/7 activity can also be measured using fluorogenic substrates to confirm induction of apoptosis. Gene expression analysis by qRT-PCR can confirm downregulation of CRC and MYCN. |
| Animal Protocol |
Animal/Disease Models: Kelly NB cell xenograft in NSG mice [1]
Doses: 40 mg/kg Route of Administration: intraperitoneal (ip) injection; one time/day for 21 days Experimental Results: inhibited tumor growth and prolonged survival. Animal/Disease Models: CD1 mice[1] Doses: 10 mg/kg Route of Administration: intraperitoneal (ip) injection (pharmacokinetic/PK/PK analysis) Experimental Results: The half-life in mouse serum is 13.3 (±3.37 SD) hrs (hrs (hours)), Cmax is 7 μmol/ L. For in vivo efficacy studies, NSG immunodeficient mice are subcutaneously implanted with Kelly neuroblastoma cells. When tumors reach approximately 100-200 mm³, mice are randomized and treated with JQAD1 via intraperitoneal or intravenous administration at doses determined from pharmacokinetic studies. Tumor volumes are measured twice weekly. At study endpoint, tumors are collected for Western blot analysis of EP300 degradation and H3K27ac suppression, as well as for histopathological examination and gene expression analysis. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of JQAD1 have been evaluated in preclinical studies. The compound is soluble in DMSO at 100 mg/mL (107.18 mM) and in ethanol at 25 mg/mL (26.79 mM). Storage is recommended at -20°C. The compound is a solid at room temperature. Further detailed PK parameters including half-life, bioavailability, clearance, and tissue distribution would be available in the primary literature and compound documentation.
|
| Toxicity/Toxicokinetics |
Toxicological data for JQAD1 have not been extensively reported in the available literature. In preclinical studies, the compound has been evaluated in mouse xenograft models where it suppresses tumor growth. The compound is for research use only and is not for human or veterinary use. Standard laboratory safety precautions should be followed when handling JQAD1. Comprehensive toxicology studies would be required for clinical development.
|
| References | |
| Additional Infomation |
JQAD1 is a CRBN-dependent PROTAC that selectively degrades EP300 (p300) with a DC50 ≤ 31.6 nM. It is composed of the EP300 inhibitor A485 linked to a cereblon E3 ligase ligand. JQAD1 selectively degrades p300 over CBP in MYCN-amplified neuroblastoma cells, suppresses H3K27ac modification, induces apoptosis, and inhibits tumor growth in xenograft models. It is a research tool for studying EP300 biology and is not approved for clinical use.
|
| Molecular Formula |
C48H52F4N6O9
|
|---|---|
| Molecular Weight |
932.954906463623
|
| Exact Mass |
932.373
|
| CAS # |
2417097-18-6
|
| PubChem CID |
162615894
|
| Appearance |
Light yellow to green yellow solid powder
|
| LogP |
7.6
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
14
|
| Rotatable Bond Count |
20
|
| Heavy Atom Count |
67
|
| Complexity |
1860
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
O=C1N(C(=O)O[C@]21CCC1=CC(NC(=O)CCCCCCCCCCCNC3=CC=C4C(=O)N(C5CCC(=O)NC5=O)C(=O)C4=C3)=CC=C21)CC(=O)N([C@@H](C)C(F)(F)F)CC1C=CC(F)=CC=1
|
| InChi Key |
TWCIGBYYSZQAAA-GWWVHQGYSA-N
|
| InChi Code |
InChI=1S/C48H52F4N6O9/c1-29(48(50,51)52)56(27-30-12-14-32(49)15-13-30)41(61)28-57-45(65)47(67-46(57)66)23-22-31-25-34(17-19-37(31)47)54-39(59)11-9-7-5-3-2-4-6-8-10-24-53-33-16-18-35-36(26-33)44(64)58(43(35)63)38-20-21-40(60)55-42(38)62/h12-19,25-26,29,38,53H,2-11,20-24,27-28H2,1H3,(H,54,59)(H,55,60,62)/t29-,38?,47+/m0/s1
|
| Chemical Name |
12-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]-N-[(5R)-3-[2-[(4-fluorophenyl)methyl-[(2S)-1,1,1-trifluoropropan-2-yl]amino]-2-oxoethyl]-2,4-dioxospiro[1,3-oxazolidine-5,1'-2,3-dihydroindene]-5'-yl]dodecanamide
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~107.19 mM)
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0719 mL | 5.3593 mL | 10.7187 mL | |
| 5 mM | 0.2144 mL | 1.0719 mL | 2.1437 mL | |
| 10 mM | 0.1072 mL | 0.5359 mL | 1.0719 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
