dBET6 | CAS# 1950634-92-0 | BET bromodomain proteins degrader

MedKoo Cat#: 563787 | Name: dBET6

Description:

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

dBET6 is a novel degrader of BET bromodomain proteins. dBET6 prompts a collapse of global elongation that phenocopies CDK9 inhibition.

Chemical Structure

dBET6

CAS#1950634-92-0

Theoretical Analysis

MedKoo Cat#: 563787

Name: dBET6

CAS#: 1950634-92-0

Chemical Formula: C42H45ClN8O7S

Exact Mass: 840.2820

Molecular Weight: 841.38

Elemental Analysis: C, 59.96; H, 5.39; Cl, 4.21; N, 13.32; O, 13.31; S, 3.81

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,350.00	Ready to ship
500mg	USD 2,650.00	Ready to ship
1g	USD 3,650.00	2 Weeks

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Synonym

dBET6; d BET6; d-BET6

IUPAC/Chemical Name

2-((S)-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-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)octyl)-acetamide

InChi Key

JGQPZPLJOBHHBK-UFXYQILXSA-N

InChi Code

InChI=1S/C42H45ClN8O7S/c1-23-24(2)59-42-35(23)37(26-13-15-27(43)16-14-26)46-29(38-49-48-25(3)50(38)42)21-33(53)44-19-8-6-4-5-7-9-20-45-34(54)22-58-31-12-10-11-28-36(31)41(57)51(40(28)56)30-17-18-32(52)47-39(30)55/h10-16,29-30H,4-9,17-22H2,1-3H3,(H,44,53)(H,45,54)(H,47,52,55)/t29-,30?/m0/s1

SMILES Code

O=C(NCCCCCCCCNC(COC1=CC=CC(C(N2C(CC3)C(NC3=O)=O)=O)=C1C2=O)=O)C[C@H]4C5=NN=C(C)N5C6=C(C(C)=C(C)S6)C(C7=CC=C(Cl)C=C7)=N4

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

>3 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

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#T20D10P20

QC Data

View QC data: current batch, Lot#T20D10P20

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

dBET6 is a highly potent, selective and cell-permeable degrader of BET based on PROTAC, with an IC50 of 14 nM that has antitumor activity.

In vitro activity:

To gain insight into BET protein dependency of GBM cells, we assessed the consequence of dBET6-induced BET protein depletion on RNA-Pol2 function and epigenetic modifications. Recruitment of BET proteins to hyperacetylated chromatin potentiates active transcription. Herein, it was observed that dBET6 inhibited phosphorylation of RNA-Pol2 (especially Ser2 at the C-terminal domain) with a moderate decrease of total RNA-Pol2 (Fig. 5A). RNA-Pol2 ChIP-seq analysis revealed that dBET6 treatment reduced the average RNA-Pol2 occupancy in both promoter/transcription start site (TSS) and gene body, and resulted in a shift of the average RNA-Pol2 peak center toward the gene body (Fig. 5 B and C and SI Appendix, Fig. S5A). Further, dBET6 treatment substantially increased the RNA-Pol2 pausing indexes of genes whose promoter/TSS regions did not show drastic reduction of RNA-Pol2 binding (Fig. 5D). These data indicate that dBET6 inhibits both RNA-Pol2 loading and elongation. In parallel to defective transcription, dBET6 treatment reduced overall levels of active histone marks (H3K27ac and H3K4me3), whereas it moderately elevated the repressive histone marks (H3K27me3 and H3K9me3) (SI Appendix, Fig. S5B), implying that initial recruitment of BET proteins contributes to the maintenance of a permissive chromatin state. Proc Natl Acad Sci U S A. 2018 May 29; 115(22): E5086–E5095. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984485/

In vivo activity:

Next, the in vivo efficacy of JQ1 and dBET6 were compared in a disseminated mouse model of T-ALL. SUPT11 cells were stably transduced to express luciferase and mCherry to allow monitoring of disease burden. After 2 weeks, mice with detectable engraftment were randomized into groups and treated either with vehicle control, JQ1 (7.5 mg/kg), or dBET6 (7.5 mg/kg) twice daily for a total of 18 days. Pharmacokinetic studies indicated adequate exposure to dBET6 (Figures S2G and S2H). We quantified leukemic burden via measuring total body luminescence, which revealed a significant reduction upon dBET6 treatment (Figures 2G and S4J). This was confirmed for dBET6 via post-mortem analysis of leukemic burden in the bone marrow (Figure 2H). In vivo degradation of BRD4 in leukemic bone marrow was shown 3 hr post treatment via immunoblot (Figure 2I). Finally, it was set out to explore if continuous treatment of dBET6 over a period of 14 days would lead to a survival benefit in an aggressive, disseminated model of T-ALL (MOLT4). Again, mice treated with dBET6 (7.5 mg/kg BID) exhibited a significant survival benefit compared to mice treated with vehicle control or JQ1 (20 mg/kg QD; Figure 2J). Mol Cell. Author manuscript; available in PMC 2018 Jul 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663500/

	Solvent	mg/mL	mM
Solubility
	DMSO	60.0	71.32
	Ethanol	35.0	41.60

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 841.38 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.

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:

1. Xu L, Chen Y, Mayakonda A, Koh L, Chong YK, Buckley DL, Sandanaraj E, Lim SW, Lin RY, Ke XY, Huang ML, Chen J, Sun W, Wang LZ, Goh BC, Dinh HQ, Kappei D, Winter GE, Ding LW, Ang BT, Berman BP, Bradner JE, Tang C, Koeffler HP. Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma. Proc Natl Acad Sci U S A. 2018 May 29;115(22):E5086-E5095. doi: 10.1073/pnas.1712363115. Epub 2018 May 15. PMID: 29764999; PMCID: PMC5984485. 2. Winter GE, Mayer A, Buckley DL, Erb MA, Roderick JE, Vittori S, Reyes JM, di Iulio J, Souza A, Ott CJ, Roberts JM, Zeid R, Scott TG, Paulk J, Lachance K, Olson CM, Dastjerdi S, Bauer S, Lin CY, Gray NS, Kelliher MA, Churchman LS, Bradner JE. BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment. Mol Cell. 2017 Jul 6;67(1):5-18.e19. doi: 10.1016/j.molcel.2017.06.004. Epub 2017 Jun 29. PMID: 28673542; PMCID: PMC5663500.

In vitro protocol:

In vivo protocol:

1. Winter GE, Mayer A, Buckley DL, Erb MA, Roderick JE, Vittori S, Reyes JM, di Iulio J, Souza A, Ott CJ, Roberts JM, Zeid R, Scott TG, Paulk J, Lachance K, Olson CM, Dastjerdi S, Bauer S, Lin CY, Gray NS, Kelliher MA, Churchman LS, Bradner JE. BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment. Mol Cell. 2017 Jul 6;67(1):5-18.e19. doi: 10.1016/j.molcel.2017.06.004. Epub 2017 Jun 29. PMID: 28673542; PMCID: PMC5663500.

1: Xu L, Chen Y, Mayakonda A, Koh L, Chong YK, Buckley DL, Sandanaraj E, Lim SW, Lin RY, Ke XY, Huang ML, Chen J, Sun W, Wang LZ, Goh BC, Dinh HQ, Kappei D, Winter GE, Ding LW, Ang BT, Berman BP, Bradner JE, Tang C, Koeffler HP. Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma. Proc Natl Acad Sci U S A. 2018 May 29;115(22):E5086-E5095. doi: 10.1073/pnas.1712363115. Epub 2018 May 15. PubMed PMID: 29764999; PubMed Central PMCID: PMC5984485. 2: Winter GE, Mayer A, Buckley DL, Erb MA, Roderick JE, Vittori S, Reyes JM, di Iulio J, Souza A, Ott CJ, Roberts JM, Zeid R, Scott TG, Paulk J, Lachance K, Olson CM, Dastjerdi S, Bauer S, Lin CY, Gray NS, Kelliher MA, Churchman LS, Bradner JE. BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment. Mol Cell. 2017 Jul 6;67(1):5-18.e19. doi: 10.1016/j.molcel.2017.06.004. Epub 2017 Jun 29. PubMed PMID: 28673542; PubMed Central PMCID: PMC5663500.