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Discovery of novel CBP bromodomain inhibitors through TR-FRET-based high-throughput screening.
- Source :
-
Acta pharmacologica Sinica [Acta Pharmacol Sin] 2020 Feb; Vol. 41 (2), pp. 286-292. Date of Electronic Publication: 2019 Jun 28. - Publication Year :
- 2020
-
Abstract
- The cAMP-responsive element binding protein (CREB) binding protein (CBP) and adenoviral E1A-binding protein (P300) are two closely related multifunctional transcriptional coactivators. Both proteins contain a bromodomain (BrD) adjacent to the histone acetyl transferase (HAT) catalytic domain, which serves as a promising drug target for cancers and immune system disorders. Several potent and selective small-molecule inhibitors targeting CBP BrD have been reported, but thus far small-molecule inhibitors targeting BrD outside of the BrD and extraterminal domain (BET) family are especially lacking. Here, we established and optimized a TR-FRET-based high-throughput screening platform for the CBP BrD and acetylated H4 peptide. Through an HTS assay against an in-house chemical library containing 20 000 compounds, compound DC&#95;CP20 was discovered as a novel CBP BrD inhibitor with an IC <subscript>50</subscript> value of 744.3 nM. This compound bound to CBP BrD with a K <subscript>D</subscript> value of 4.01 μM in the surface plasmon resonance assay. Molecular modeling revealed that DC&#95;CP20 occupied the Kac-binding region firmly through hydrogen bonding with the conserved residue N1168. At the celluslar level, DC&#95;CP20 dose-dependently inhibited the proliferation of human leukemia MV4-11 cells with an IC <subscript>50</subscript> value of 19.2 μM and markedly downregulated the expression of the c-Myc in the cells. Taken together, the discovery of CBP BrD inhibitor DC&#95;CP20 provides a novel chemical scaffold for further medicinal chemistry optimization and a potential chemical probe for CBP-related biological function research. In addition, this inhibitor may serve as a promising therapeutic strategy for MLL leukemia by targeting CBP BrD protein.
- Subjects :
- Antineoplastic Agents administration & dosage
Antineoplastic Agents chemistry
Binding Sites
Cell Line, Tumor
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Discovery methods
Fluorescence Resonance Energy Transfer
Humans
Inhibitory Concentration 50
Leukemia pathology
Models, Molecular
Protein Domains
Small Molecule Libraries
Antineoplastic Agents pharmacology
CREB-Binding Protein antagonists & inhibitors
High-Throughput Screening Assays
Leukemia drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1745-7254
- Volume :
- 41
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Acta pharmacologica Sinica
- Publication Type :
- Academic Journal
- Accession number :
- 31253937
- Full Text :
- https://doi.org/10.1038/s41401-019-0256-2