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Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors
- Source :
- Journal of medicinal chemistry. 62(18)
- Publication Year :
- 2019
-
Abstract
- BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4 harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one structure. Among them, compound 19 was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound 19 is a potential BET protein drug candidate for the treatment of cancer.
- Subjects :
- Male
BRD4
hERG
Protein domain
Mice, Nude
Antineoplastic Agents
Cell Cycle Proteins
Mice, SCID
Pharmacology
Crystallography, X-Ray
01 natural sciences
03 medical and health sciences
chemistry.chemical_compound
Inhibitory Concentration 50
Mice
Protein Domains
In vivo
Neoplasms
Drug Discovery
Animals
Humans
030304 developmental biology
Cell Proliferation
0303 health sciences
Mice, Inbred BALB C
Mice, Inbred ICR
biology
Molecular Structure
Chemistry
Drug discovery
Nuclear Proteins
Proteins
0104 chemical sciences
Bromodomain
010404 medicinal & biomolecular chemistry
Drug Design
biology.protein
Microsomes, Liver
Molecular Medicine
Peptides
Linker
Lead compound
Neoplasm Transplantation
Transcription Factors
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 62
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....20b30e35bd2cad52ad21608527b3d40d