Sameshima, Tomoya published the artcileDiscovery of an Irreversible and Cell-Active BCL6 Inhibitor Selectively Targeting Cys53 Located at the Protein-Protein Interaction Interface, Recommanded Product: 3-Chloro-4-fluoronitrobenzene, the publication is Biochemistry (2018), 57(8), 1369-1379, database is CAplus and MEDLINE.
B-cell lymphoma 6 (BCL6) is the most frequently involved oncogene in diffuse large B-cell lymphomas (DLBCLs). BCL6 shows potent transcriptional repressor activity through interactions with its corepressors, such as BCL6 corepressor (BCOR). The inhibition of the protein-protein interaction (PPI) between BCL6 and its corepressors suppresses the growth of BCL6-dependent DLBCLs, thus making BCL6 an attractive drug target for lymphoma treatments. However, potent small-mol. PPI inhibitor identification remains challenging because of the lack of deep cavities at PPI interfaces. This paper reports the discovery of a potent, cell-active, small-mol. BCL6 inhibitor, BCL6-i (8), that operates through irreversible inhibition. First, we synthesized an irreversible lead compound 4, which targets Cys53 in a cavity on the BCL6 BTB domain dimer by introducing an irreversible warhead to a high-throughput screening hit compound 1. Further chem. optimization of 4 based on kinact/KI evaluation produced BCL6-i with a kinact/KI value of 1.9 × 104 M-1s-1, corresponding to a 670-fold improvement in potency compared to 4. By exploiting the property of irreversible inhibition, engagement of BCL6-i to intracellular BCL6 was confirmed. BCL6-i showed intracellular PPI inhibitory activity between BCL6 and its corepressors, thus resulting in BCL6-dependent DLBCL cell-growth inhibition. BCL6-i is a cell-active chem. probe with the most potent BCL6 inhibitory activity reported to date. The discovery process of BCL6-i illustrates the utility of irreversible inhibition for identifying potent chem. probes for intractable target proteins.
Biochemistry published new progress about 350-30-1. 350-30-1 belongs to chlorides-buliding-blocks, auxiliary class Fluoride,Chloride,Nitro Compound,Benzene, name is 3-Chloro-4-fluoronitrobenzene, and the molecular formula is C6H3ClFNO2, Recommanded Product: 3-Chloro-4-fluoronitrobenzene.
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