dBET1

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.

Product information

CAS Number: 1799711-21-9

Molecular Weight: 785.27

Formula: C38H37ClN8O7S

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

Smiles: CC(=O)N(CCCCNC(=O)COC1=CC=CC2=C1C(=O)N(C1CCC(=O)NC1=O)C2=O)C1N=C(C2=C(SC(C)=C2C)N2C1=NN=C2C)C1C=CC(Cl)=CC=1

InChiKey: LNKVJWZPPUIOFG-UHFFFAOYSA-N

InChi: 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)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO: 100 mg/mL(127.34 mM).

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

In Vitro:

Treatment with dBET1 elicits a comparable, modest effect on MYC and PIM1 expression. Its treatment downregulates MYC and PIM1 transcription, suggestive of secondary transcriptional effects and transcription of BRD4 and BRD3 are unaffected, consistent with post-transcriptional effects. Transcription of BRD2 is affected by dBET1 and protein stability of the BRD2 gene product is influenced by dBET1. dBET1 induces a potent and superior inhibitory effect on MV4;11 cell proliferation at 24 hours (measured by ATP content, IC50 = 0.14 μM). Exposure of primary leukemic patient blasts to dBET1 elicits dose-proportionate depletion of BRD4 and induction of apoptosis. dBET1-mediated targeted degradation of BET proteins robustly dampens pro-inflammatory responses in LPS-stimulated microglia, that is, depletion of BRD2 and BRD4 with dBET1 is associated with dramatically reduced LPS-induced COX-2 and iNOS protein levels and pro-inflammatory gene transcription of Nos2, Il-1β, Il-6, Tnfα, Ccl2, Ptgs2, and Mmp9.

In Vivo:

Administration of dBET1 attenuates tumor progression and decreases tumor weight assessed post-mortem in murine xenograft model of human MV4;11 leukemia cells. Pharmacokinetic studies of dBET1 (50 mg/kg IP) corroborate adequate drug exposure in vivo (Cmax = 392 nM, Tmax=0.5 hr, terminal t1/2=6.69 hr, AUClast=2109 hr*ng/ml, AUCINF=295 hr*ng/ml). Two weeks of dBET1 is well tolerated by mice without a meaningful effect on weight, white blood count, hematocrit or platelet count.

References:

1. DeMars KM, et al. Biochem Biophys Res Commun. 2018, 497(1):410-415.
2. Georg E. Winter, et al. Science. 2015, 348(6241): 1376-1381.

Products are for research use only. Not for human use.