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MedKoo Cat#: 562430 | Name: dBET1
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

dBET1 is a potent BRD4 degrader (IC50=20 nM), and competitive antagonist of BET bromodomains to hijack the Cereblon E3 ubiquitin ligase complex. dBET1 is a hybrid molecule that combines (+)-JQ1 and thalidomide.1 The JQ1 portion facilitates binding of dBET1 to the bromodomains of BET family transcriptional activators. The thalidomide moiety drives proteasomal degradation, as phthalimides bind cereblon to create a substrate recognition site for E3 protein ligase complex-mediated ubiquitination.

Chemical Structure

dBET1
dBET1
CAS#1799711-21-9

Theoretical Analysis

MedKoo Cat#: 562430

Name: dBET1

CAS#: 1799711-21-9

Chemical Formula: C38H37ClN8O7S

Exact Mass: 784.2194

Molecular Weight: 785.27

Elemental Analysis: C, 58.12; H, 4.75; Cl, 4.51; N, 14.27; O, 14.26; S, 4.08

Price and Availability

Size Price Availability Quantity
5mg USD 120.00 Ready to ship
10mg USD 215.00 Ready to ship
25mg USD 450.00 Ready to ship
50mg USD 800.00 Ready to ship
100mg USD 1,360.00 Ready to ship
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Related CAS #
No Data
Synonym
dBET1; d-BET-1; d BET 1; dBET-1; dBET 1; JQ1-Thalidomide conjugate;
IUPAC/Chemical Name
N-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)butyl)acetamide
InChi Key
LNKVJWZPPUIOFG-UHFFFAOYSA-N
InChi Code
InChI=1S/C38H37ClN8O7S/c1-19-20(2)55-38-30(19)32(23-10-12-24(39)13-11-23)42-33(34-44-43-21(3)46(34)38)45(22(4)48)17-6-5-16-40-29(50)18-54-27-9-7-8-25-31(27)37(53)47(36(25)52)26-14-15-28(49)41-35(26)51/h7-13,26,33H,5-6,14-18H2,1-4H3,(H,40,50)(H,41,49,51)
SMILES Code
CC(N(C1C2=NN=C(C)N2C3=C(C(C)=C(C)S3)C(C4=CC=C(Cl)C=C4)=N1)CCCCNC(COC5=CC=CC(C(N6C(CC7)C(NC7=O)=O)=O)=C5C6=O)=O)=O
Appearance
Solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. The transcriptional coactivator BRD4 is a protein critical for cancer cell growth and survival.
Biological target:
dBET1 is a potent BRD4 protein degrader based on PROTAC technology with an EC50 of 430 nM.
In vitro activity:
To functionally assess the effect of dBET1 on BRD4 stability in cells, a human AML cell line (MV4;11) was treated for 18 hours with increasing concentrations of dBET1 and assayed endogenous BRD4 levels by immunoblot. Pronounced loss of BRD4 (> 85%) was observed with concentrations of dBET1 as low as 100 nM (Fig 1H). The epimeric control dBET1(R) compound that lacks BRD4 binding (> 300 fold weaker binding in homogenous assays) was inactive, demonstrating that BRD4 degradation requires target protein engagement (Fig S2A, B). The kinetics of BRD4 degradation were next determined in a time course experiment using 100 nM dBET1 in MV4;11 cells. Marked depletion of BRD4 was observed at 1 hour and complete degradation was observed at 2 hours of treatment (Fig 1I). A partial recovery in BRD4 abundance at 24 hours establishes the possibility of compound metabolic instability, a recognized liability of phthalimide drug molecules. To quantify dose-responsive effects on BRD4 protein stability, a cell-count normalized, immunofluorescence-based high-content assay in an adherent human cancer cell line was developed (SUM149 breast cancer cells; Fig 1J). Potent depletion of total BRD4 was observed for dBET1 (EC50 = 430 nM) without apparent activity for dBET1(R). These observations were confirmed by immunoblot in SUM149, which have been used for baseline normalization of the assay (Fig S2C, D). Additional cultured adherent and non-adherent human cancer cell lines showed comparable response (SUM159, MOLM13; Fig S3). Reference: Science. 2015 Jun 19;348(6241):1376-81. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25999370/
In vivo activity:
To model the therapeutic opportunity of BRD4 degradation in vivo, the tolerability and anti-tumor efficacy of repeat-dose dBET1 was evaluated in an established murine xenograft model of human MV4;11 leukemia cells. Tumor-bearing mice were treated with dBET1 administered by intraperitoneal injection (50 mg/kg daily) or vehicle control. After 14 days of therapy a first tumor reached institutional limits for tumor size, and the study was terminated for comparative assessment of efficacy and modulation of BRD4 stability and function. Administration of dBET1 attenuated tumor progression as determined by serial volumetric measurement (Fig 4H), and decreased tumor weight assessed post-mortem (Fig 4I). Acute pharmacodynamic degradation of BRD4 was observed four hours after a first or second daily treatment with dBET1 (50 mg/kg IP) by immunoblot (Fig 4J), accompanied by downregulation of MYC (Fig 4J). These findings were confirmed by quantitative immunohistochemistry for BRD4 and MYC following repeat-dose exposure to dBET1 for 14 days (Fig 4K). A statistically significant destabilization of BRD4, downregulation of MYC and inhibition of proliferation (Ki67 staining) was observed with dBET1 compared to vehicle control in excised tumors (Fig 4K, ,4L).4L). Pharmacokinetic studies of dBET1 (50 mg/kg IP) corroborate adequate drug exposure in vivo (Cmax = 392 nM; SFig 7B), above the EC50 for BRD4 knock-down observed in vitro (<100 nM). Notably, two weeks of dBET1 was well tolerated by mice without a meaningful effect on weight, white blood count, hematocrit or platelet count (SFig 7C, 7D). Reference: Science. 2015 Jun 19;348(6241):1376-81. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25999370/
Solvent mg/mL mM
Solubility
DMSO 43.3 55.18
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 785.27 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol:
1. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015 Jun 19;348(6241):1376-81. doi: 10.1126/science.aab1433. Epub 2015 May 21. PMID: 25999370; PMCID: PMC4937790. 2. Otto C, Schmidt S, Kastner C, Denk S, Kettler J, Müller N, Germer CT, Wolf E, Gallant P, Wiegering A. Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells. Neoplasia. 2019 Nov;21(11):1110-1120. doi: 10.1016/j.neo.2019.10.003. Epub 2019 Nov 14. PMID: 31734632; PMCID: PMC6888720.
In vivo protocol:
1. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015 Jun 19;348(6241):1376-81. doi: 10.1126/science.aab1433. Epub 2015 May 21. PMID: 25999370; PMCID: PMC4937790.
1: DeMars KM, Yang C, Castro-Rivera CI, Candelario-Jalil E. Selective degradation of BET proteins with dBET1, a proteolysis-targeting chimera, potently reduces pro-inflammatory responses in lipopolysaccharide-activated microglia. Biochem Biophys Res Commun. 2018 Feb 26;497(1):410-415. doi: 10.1016/j.bbrc.2018.02.096. Epub 2018 Feb 12. PMID: 29448097. 2: DeMars KM, Yang C, Candelario-Jalil E. Neuroprotective effects of targeting BET proteins for degradation with dBET1 in aged mice subjected to ischemic stroke. Neurochem Int. 2019 Jul;127:94-102. doi: 10.1016/j.neuint.2019.03.004. Epub 2019 Mar 11. PMID: 30872008. 3: Akuffo AA, Alontaga AY, Metcalf R, Beatty MS, Becker A, McDaniel JM, Hesterberg RS, Goodheart WE, Gunawan S, Ayaz M, Yang Y, Karim MR, Orobello ME, Daniel K, Guida W, Yoder JA, Rajadhyaksha AM, Schönbrunn E, Lawrence HR, Lawrence NJ, Epling-Burnette PK. Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblon. J Biol Chem. 2018 Apr 20;293(16):6187-6200. doi: 10.1074/jbc.M117.816868. Epub 2018 Feb 15. PMID: 29449372; PMCID: PMC5912449. 4: Bauer K, Berger D, Zielinski CC, Valent P, Grunt TW. Hitting two oncogenic machineries in cancer cells: cooperative effects of the multi-kinase inhibitor ponatinib and the BET bromodomain blockers JQ1 or dBET1 on human carcinoma cells. Oncotarget. 2018 May 29;9(41):26491-26506. doi: 10.18632/oncotarget.25474. PMID: 29899872; PMCID: PMC5995173. 5: Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015 Jun 19;348(6241):1376-81. doi: 10.1126/science.aab1433. Epub 2015 May 21. PMID: 25999370; PMCID: PMC4937790. 6: Sahni JM, Keri RA. Targeting bromodomain and extraterminal proteins in breast cancer. Pharmacol Res. 2018 Mar;129:156-176. doi: 10.1016/j.phrs.2017.11.015. Epub 2017 Nov 16. PMID: 29154989; PMCID: PMC5828951. 7: Otto C, Schmidt S, Kastner C, Denk S, Kettler J, Müller N, Germer CT, Wolf E, Gallant P, Wiegering A. Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells. Neoplasia. 2019 Nov;21(11):1110-1120. doi: 10.1016/j.neo.2019.10.003. Epub 2019 Nov 14. PMID: 31734632; PMCID: PMC6888720. 8: Dai X, Gan W, Li X, Wang S, Zhang W, Huang L, Liu S, Zhong Q, Guo J, Zhang J, Chen T, Shimizu K, Beca F, Blattner M, Vasudevan D, Buckley DL, Qi J, Buser L, Liu P, Inuzuka H, Beck AH, Wang L, Wild PJ, Garraway LA, Rubin MA, Barbieri CE, Wong KK, Muthuswamy SK, Huang J, Chen Y, Bradner JE, Wei W. Prostate cancer- associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat Med. 2017 Sep;23(9):1063-1071. doi: 10.1038/nm.4378. Epub 2017 Aug 14. PMID: 28805820; PMCID: PMC5625299.