CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation

Differentially screening the Fr-PPIChem chemical library on the bromodomain and extra-terminal (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...

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Veröffentlicht in:	Journal of medicinal chemistry 2022-04, Vol.65 (7), p.5660-5674
Hauptverfasser:	Carrasco, Kendall, Montersino, Camille, Derviaux, Carine, Saez-Ayala, Magali, Hoffer, Laurent, Restouin, Audrey, Castellano, Rémy, Casassa, Justine, Roche, Philippe, Pasquier, Eddy, Combes, Sébastien, Morelli, Xavier, Collette, Yves, Betzi, Stéphane
Format:	Artikel
Sprache:	eng
Schlagworte:	Biochemistry, Molecular Biology Cancer Cell Cycle Proteins Life Sciences Nuclear Proteins Protein Domains Small Molecule Libraries - chemistry Structural Biology Structure-Activity Relationship Transcription Factors
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creator	Carrasco, Kendall Montersino, Camille Derviaux, Carine Saez-Ayala, Magali Hoffer, Laurent Restouin, Audrey Castellano, Rémy Casassa, Justine Roche, Philippe Pasquier, Eddy Combes, Sébastien Morelli, Xavier Collette, Yves Betzi, Stéphane
description	Differentially screening the Fr-PPIChem chemical library on the bromodomain and extra-terminal (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 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 modulate the anti-leukemic 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 bromodomain (BD) cavity and its potential as a starting scaffold for the development of potent and selective bromodomain inhibitors.
doi_str_mv	10.1021/acs.jmedchem.1c02168
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Structure–activity relationship (SAR) and hit-to-lead approaches allowed us to develop CRCM5484, a 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 modulate the anti-leukemic activity in combination with various FDA-approved and/or in-development drugs in a cell- and context-dependent differential manner. 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Med. Chem</addtitle><description>Differentially screening the Fr-PPIChem chemical library on the bromodomain and extra-terminal (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 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 modulate the anti-leukemic activity in combination with various FDA-approved and/or in-development drugs in a cell- and context-dependent differential manner. 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subjects	Biochemistry, Molecular Biology Cancer Cell Cycle Proteins Life Sciences Nuclear Proteins Protein Domains Small Molecule Libraries - chemistry Structural Biology Structure-Activity Relationship Transcription Factors
title	CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation
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