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CRCM5484: A BET- BDII Selective Compound With Differential Anti-Leukemic Drug Modulation
- Source :
- Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, 2022, pp.acs.jmedchem.1c02168. ⟨10.1021/acs.jmedchem.1c02168⟩
- Publication Year :
- 2022
- Publisher :
- HAL CCSD, 2022.
-
Abstract
- 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 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 BD cavity and its potential as starting scaffold for the development of potent and selective bromodomain inhibitors.
- Subjects :
- potentiation
diversity-oriented library
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]
[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]
bone-marrow-derived stromal cell conditioned medium
Nuclear Proteins
Bromodomain
Cell Cycle Proteins
[SDV.CAN]Life Sciences [q-bio]/Cancer
focused library
drug discovery
Small Molecule Libraries
protein-protein interaction
BDII selective inhibitor
Structure-Activity Relationship
modulation
Protein Domains
[SDV.CAN] Life Sciences [q-bio]/Cancer
hit-to-lead
[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Molecular Medicine
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
optimization
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, 2022, pp.acs.jmedchem.1c02168. ⟨10.1021/acs.jmedchem.1c02168⟩
- Accession number :
- edsair.doi.dedup.....0378e958b388b76b3d8b2be970b66b5e