PROTAC BRD2/BRD4 degrader-1

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Size

Price

Stock

Quantity

$--

In stock

Solubility

Soluble in DMSO

IUPACName

N-[4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]butyl]-3-[6-[(2-methoxyphenyl)sulfonylamino]-1-methyl-2-oxobenzo[cd]indol-4-yl]propanamide

Synonyms

NSC-812346; N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-3-(6-((2-methoxyphenyl)sulfonamido)-1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)propanamide; Benz[cd]indole-4-propanamide, N-[4-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]butyl]-1,2-dihydro-6-[[(2-methoxyphenyl)sulfonyl]amino]-1-methyl-2-oxo-; N-[4-[[2-(2,6-Dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]butyl]-1,2-dihydro-6-[[(2-methoxyphenyl)sulfonyl]amino]-1-methyl-2-oxobenz[cd]indole-4-propanamide

Density

1.466±0.06 g/cm3

InChI Key

DCPKSVYPNGBDSB-UHFFFAOYSA-N

InChI

InChI=1S/C39H38N6O9S/c1-44-28-14-13-26(43-55(52,53)31-11-4-3-10-30(31)54-2)24-20-22(21-25(34(24)28)37(44)49)12-16-32(46)41-19-6-5-18-40-27-9-7-8-23-35(27)39(51)45(38(23)50)29-15-17-33(47)42-36(29)48/h3-4,7-11,13-14,20-21,29,40,43H,5-6,12,15-19H2,1-2H3,(H,41,46)(H,42,47,48)

Canonical SMILES

CN1C2=C3C(=CC(=CC3=C(C=C2)NS(=O)(=O)C4=CC=CC=C4OC)CCC(=O)NCCCCNC5=CC=CC6=C5C(=O)N(C6=O)C7CCC(=O)NC7=O)C1=O

1. Discovery of novel small molecule induced selective degradation of the bromodomain and extra-terminal (BET) bromodomain protein BRD4 and BRD2 with cellular potencies.

Jiang, F., Wei, Q., Li, H., Li, H., Cui, Y., Ma, Y., Chen, H., Cao, P., Lu, T. and Chen, Y., 2020. Bioorganic & Medicinal Chemistry, 28(1), p.115181.

The BET proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation and can be degraded by proteolysis-targeting chimeras (PROTACs) for BET proteins. However, the lack of intra-BET proteins selectivity limits the scope of current degraders as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We describe herein the design, synthesis, and evaluation of PROTAC BET degraders, based on the BET inhibitor with selectivity for the first Bromodomain benzo[cd]indole-2-one, alkylamide linker and cereblon ligand thalidomide. Compound 15 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 and BRD2 over BRD3, which not only effectively inhibits cell growth in human acute leukemia cell lines, but also very effective in inhibiting solid tumors with low cytotoxic effect in the cell profiles of NCI 60 cell lines. Remarkable dependency on linker length was observed for BRD4-degrading and c-Myc-driven antiproliferative activities in acute myeloid leukemia cell line MV4-11. The small-molecular 15 represents a novel, potent, and selective class of BRD4 and BRD2 degraders for the development of therapeutics to treat cancers.

What kind of advantages does it has?

BRD4 and BRD2 are overactive in many cancers, and their inhibition has shown promising anti-tumor effects in various cancer models. PROTAC BRD2/BRD4 degrader-1's ability to degrade these proteins could potentially lead to more effective cancer treatments than traditional inhibitors. Additionally, its selectivity towards BRD4 and BRD2 over other closely related proteins like BRD3 could potentially reduce side effects.

22/5/2017

How does it work?

Unlike traditional drugs that simply inhibit BRD4 and BRD2 activity, PROTAC BRD2/BRD4 degrader-1 actually recruits these proteins to another protein called cereblon. Cereblon acts like a garbage disposal for the cell, tagging the bound BRD4 and BRD2 for degradation. This results in a more pronounced and long-lasting reduction in BRD4 and BRD2 levels compared to traditional inhibitors.

17/1/2023

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* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂