406232-64-2

Upstream product

• 5731-10-2 4'-fluoro-biphenyl-4-carboxylic acid 
• 97-09-6 4-Chloro-3-nitrobenzenesulfonamide 
• 5798-75-4 Ethyl 4-bromobenzoate 
• 97-08-5 3-nitro-4-chlorosulfonyl chloride 
• 1765-93-1 4-fluoroboronic acid 
• 10540-36-0 4'-fluorobiphenyl-4-carboxylic acid ethyl ester 
• 15290-29-6 4-(trimethylsilyl)benzoic acid 
• 225916-39-2 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane 

Downstream Products

• 406228-07-7 4-((3-cyclohexylpropyl)amino)-N-((4'-fluoro(1,1'-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide 
• 1565-49-7 4-(cyclohexylamino)-3-nitrobenzenesulfonamide 
• 406233-14-5 N-(4'-fluorobiphenyl-4-carbonyl)-4-(2-hydroxyethylamino)-3-nitrobenzenesulfonamide 
• 406228-21-5 4-((2-(benzylsulfanyl)ethyl)amino)-N-((4'-fluoro(1,1'-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide 

Relevant academic research and scientific papers

Discovery of a potent inhibitor of the antiapoptotic protein Bcl-X L from NMR and parallel synthesis

The antiapoptotic proteins Bcl-xL and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This makes Bcl-xL, and Bcl-2 attractive targets for the development of potential anticancer agents, Here we describe the structure-based discovery of a potent Bcl-xL inhibitor directed at a hydrophobic groove on the surface of the protein. This groove represents the binding site for BH3 peptides from proapoptotic Bcl-2 family members such as Bak and Bad. Application of NMR-based screening yielded an initial biaryl acid with an affinity (Kd) of ～300 μM for the protein. Following the classical "SAR by NMR" approach, a second-site ligand was identified that bound proximal to the first-site ligand in the hydrophobic groove. From NMR-based structural studies and parallel synthesis, a potent ligand was obtained, which binds to Bcl-xL with an inhibition constant (K i) of 36 ± 2 nM.

Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo

Development of a rationally designed potentiator of cancer chemotherapy, via inhibition of Bcl-XL function, is described. Lead compounds generated by NMR screening and directed parallel synthesis displayed sub-μM binding but were strongly deactivated in the presence of serum. The dominant component of serum deactivation was identified as domain III of human serum albumin (HSA); NMR solution structures of inhibitors bound to both Bcl-X L and HSA domain III indicated two potential optimization sites for separation of affinities. Modifications at both sites resulted in compounds with improved Bcl-XL binding and greatly increased activity in the presence of human serum, culminating in 73R, which bound to Bcl-XL with a Ki of 0.8 μM. In a cellular assay 73R reversed the protection afforded by Bcl-XL overexpression against cytokine deprivation in FL5.12 cells with an EC50 of 0.47 μM. 73R showed little effect on the viability of the human non small cell lung cancer cell line A549. However, consistent with the proposed mechanism, 73R potentiated the activity of paclitaxel and UV irradiation in vitro and potentiated the antitumor efficacy of paclitaxel in a mouse xenograft model.

N-Acylsulfonamide apoptosis promoters

N-Benzoyl arylsulfonamides having the formula Are BCL-X1 inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-X1 inhibiting compositions and methods of promoting apoptosis in a mammal.

N-acylsulfonamide apoptosis promoters

N-Benzoyl arylsulfonamides having the formula are BCL-Xl inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-Xl inhibiting compositions and methods of promoting apoptosis in a mammal.