1300031-52-0

Basic information

• Product Name: GSK1324726A (I-BET726)
• Synonyms: GSK1324726A;4-[(2S,4R)-1-Acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid;GSK1324726A (I-BET726);4-((2S,4R)-1-acetyl-4-(4-chlorophenylamino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid;4-[(2S,4R)-1-Acetyl-4-[(4-chlorophenyl)amino]-1,2,3,4-tetrahydro-2-methyl-6-quinolinyl]benzoic acid;I-BET726
• CAS NO: 1300031-52-0
• Molecular Formula: C₂₅H₂₃ClN₂O₃
• Molecular Weight: 434.91472
• Product Categories: Inhibitors
• Mol File: 1300031-52-0.mol
• Article Data: 7

Chemical Properties

• Boiling Point: 707.3±60.0 °C(Predicted)
• Appearance: /
• Density: 1.304±0.06 g/cm3(Predicted)
• Solubility: insoluble in H2O; ≥1.87 mg/mL in EtOH with gentle warming and ultrasonic; ≥17.7 mg/mL in DMSO
• PKA: 4.20±0.10(Predicted)
• CAS DataBase Reference: GSK1324726A (I-BET726)(CAS DataBase Reference)
• NIST Chemistry Reference: GSK1324726A (I-BET726)(1300031-52-0)
• EPA Substance Registry System: GSK1324726A (I-BET726)(1300031-52-0)

Safety Data

• Hazardous Substances Data: 1300031-52-0(Hazardous Substances Data)

Usage

Description

I-BET726 is an inhibitor of BET family proteins that binds BRD2, BRD3, and BRD4 with high affinity (IC50s = 41, 31, and 22 nM, respectively) and competes with tetra-acetylated histone 4 peptides for binding to the bromodomains of these proteins. It exhibits >1,000-fold selectivity for these proteins over other bromodomain-containing homologs. I-BET726 inhibits cell growth and induces cytotoxicity in neuroblastoma cell lines by modulating the expression of genes involved in apoptosis and Myc signaling. I-BET726 can be administered orally to animals, and it reduces tumor growth in mouse xenograft models of human neuroblastoma.

references

[1] wyce a, ganji g, smitheman kn, chung cw, korenchuk s, bai y, barbash o, le b, craggs pd, mccabe mt, kennedy-wilson km, sanchez lv, gosmini rl, parr n, mchugh cf, dhanak d, prinjha rk, auger kr, tummino pj. bet inhibition silences expression of mycn and bcl2 and induces cytotoxicity in neuroblastoma tumor models. plos one. 2013 aug 23;8(8):e72967.

Upstream product

• 1300031-82-6 N-((2SR,4RS)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)formamide 
• 1300031-83-7 N-(1-(1H-benzo[d][1,2,3]triazol-1-yl)ethyl)-4-bromoaniline 
• 1300695-51-5 ethyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate 
• 1300695-49-1 ethyl 4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoate 
• 1300031-74-6 methyl 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate 
• 1300694-19-2 ethyl 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoate 
• 1300031-70-2 methyl 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoate 
• 1300031-92-8 (3S)-3-[(4-bromophenyl)amino]butanenitrile 
• 1300031-93-9 (3S)-3-[(4-bromophenyl)amino]butanamide 
• 1300031-94-0 1-methylethyl {(3S)-3-[(4-bromophenyl)amino]butanoyl}carbamate 
• 1300031-95-1 1-methylethyl [(2S,4R)-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate 
• 1300031-98-4 1-methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate 
• 680188-22-1 (S)-3-(N-phenylamino)-butyronitrile 
• 106-39-8 bromochlorobenzene 

Downstream Products

• 1300694-21-6 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzamide 
• 1300031-70-2 methyl 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoate 
• 2010159-47-2 (2S,4R)-1-((S)-1-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)-amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-15-(tert-butyl)-1,13-dioxo-5,8,11-trioxa-2,14-diazahexadecan-16-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 
• 1403779-18-9 4-((2S,4R)-1-acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid 
• 1403778-74-4 4-((2S,4R)-1-acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide 
• 1403778-67-5 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1,3-dihydroxypropan-2-yl)benzamide 
• 1403385-02-3 2-(dimethylamino)ethyl 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoate monohydrochloride 
• 1403385-25-0 2-(dimethylamino)ethyl 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate 
• 1403385-11-4 3-(dimethylamino)propyl 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate 
• 1403385-09-0 3-((4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoyl)oxy)-N,N,N-trimethylpropan-1-aminium, formate 
• 1403385-06-7 2-((4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoyl)oxy)-N,N,N-trimethylethanaminium, formate 

Relevant articles and documents

NOVEL PROCESS

A compound or a pharmaceutically acceptable salt or solvate thereof with a molecular weight in the range 100 to 750 which inhibits the binding of the first and/or second bromodomains of human BRD-2 to 4 to acetylated lysine residues of their physiological partner which is able to: a) form a hydrogen bonding interaction in which the compound accepts a hydrogen bond from the sidechain NH2 group of the asparagine residue found at: or b) accept a water-mediated hydrogen bond in which the compound accepts a hydrogen bond from a water that is itself hydrogen-bonded to the sidechain hydroxyl of the tyrosine residue found at and c) which are also able to form a Van der Waals interaction with a lipophilic binding region of a binding pocket such that one or more heavy atoms of the said compounds lie within a 5A range of any of the heavy atoms of the following bromodomain residues which define the binding pocket: for use in the treatment of chronic autoimmune and inflammatory conditions, acute inflammatory conditions or cancer.

The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor

Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.

TETRAHYDROQUINOLINE DERIVATIVES USEFUL AS BROMODOMAIN INHIBITORS

Tetrahydroquinoline (I) derivatives, pharmaceutical compositions containing such compounds and to their use in therapy.