scholarly journals CRCM5484: A BET- BDII Selective Compound With Differential Anti-Leukemic Drug Potentiation

2021 ◽  
Author(s):  
Kendall Carrasco ◽  
Camille Montersino ◽  
Carine Derviaux ◽  
Magali Saez-Ayala ◽  
Laurent Hoffer ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Drug Sensitivity ◽  
Potent Inhibitor ◽  
Antileukemic Activity ◽  
Compound Structure ◽  
Chemical Library ◽  
Structure Activity ◽  
A Cell ◽  
Molecular Mode ◽  
Low Activity

Differentially screening the Fr-PPIChem chemical library on the BET BRD4-BDII versus -BDI bromodomains led to the discovery of a BDII selective tetrahydropyridothienopyrimidinone (THPTP)-based compound. Structure-activity relationship (SAR) and hit-to-lead approaches allowed us to develop CRCM5484, a highly potent inhibitor of BET proteins with a preferential and 475-fold selectivity for the second bromodomain of the BRD3 protein (BRD3-BDII) over its first bromodomain (BRD3-BDI). Its very low activity was demonstrated in various cell-based assays, corresponding with recent data describing other selective BDII compounds. However, screening on a drug sensitivity and resistance-profiling platform revealed its ability to potentiate the antileukemic activity in combination with various FDA-approved and/or in-development drugs in a cell- and context-dependent differential manner. Altogether, the results confirm the originality of the THPTP molecular mode of action in the BD cavity and its potential as chemical platform for the development of potent and selective bromodomain inhibitors.

Development and in vivo evaluation of fused benzazole analogs of anti-melanoma agent HA15

2021 ◽  
Author(s):  
Antoine Millet ◽  
Mauro Safir Filho ◽  
Nedra Hamouda-Tekaya ◽  
Elisa Cavazza ◽  
Patricia Abbe ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Mode Of Action ◽  
Tumor Growth Inhibition ◽  
In Vivo Evaluation ◽  
Relationship Analysis ◽  
Structure Activity ◽  
New Directions ◽  
A Cell

Background: In line with our recent discovery of an efficient anticancer thiazolebenzenesulfonamide framework HA15 (1) based on a remarkable endoplasmic reticulum stress inducement mode of action, we report herein a series of innovative constrained HA15 analogs, featuring four types of bicylic derivatives. Results: The structure–activity relationship analysis, using a cell line assay, led us to identify a novel version of HA15: a new benzothiazole derivative (10b) exhibiting important anti-melanoma effect against sensitive and resistant melanoma cells. Meanwhile, compound 10b induced a significant tumor growth inhibition in vivo with no apparent signs of toxicity. Conclusion: These results consistently open new directions to improve and develop more powerful anticancer therapeutics harboring this type of fused framework.

Triazol: a privileged scaffold for proteolysis targeting chimeras

2019 ◽  
Vol 11 (22) ◽  
pp. 2919-2973 ◽  
Author(s):  
Li-Wen Xia ◽  
Meng-Yu Ba ◽  
Wei Liu ◽  
Weyland Cheng ◽  
Chao-Ping Hu ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Anticancer Activity ◽  
Mode Of Action ◽  
Critical Analysis ◽  
Enzyme Inhibitors ◽  
Structure Activity Relationship ◽  
Target Protein ◽  
Activity Relationship ◽  
Structure Activity ◽  
Privileged Scaffold

Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure–activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.

scholarly journals Characterizing the structure–activity relationships of natural products, tanshinones, reveals their mode of action in inhibiting spleen tyrosine kinase

RSC Advances ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 2453-2461
Author(s):  
Min-Che Tung ◽  
Keng-Chang Tsai ◽  
Kit-Man Fung ◽  
Ming-Jaw Don ◽  
Tien-Sheng Tseng
Keyword(s):  
Natural Products ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Mode Of Action ◽  
Drug Target ◽  
Receptor Protein ◽  
Inflammatory Disorder ◽  
Spleen Tyrosine Kinase ◽  
Structure Activity Relationships ◽  
Structure Activity

The cytosolic non-receptor protein kinase, spleen tyrosine kinase (SYK), is an attractive drug target in autoimmune, inflammatory disorder, and cancers indications.

scholarly journals Antitubercular 2-Pyrazolylpyrimidinones: Structure–Activity Relationship and Mode-of-Action Studies

2021 ◽  
Author(s):  
Candice Soares de Melo ◽  
Vinayak Singh ◽  
Alissa Myrick ◽  
Sandile B. Simelane ◽  
Dale Taylor ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity
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