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Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases
- Source :
- Journal of Medicinal Chemistry. 63:9787-9802
- Publication Year :
- 2020
- Publisher :
- American Chemical Society (ACS), 2020.
-
Abstract
- Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with a typical kinase hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-one, we demonstrated that this rational design can produce high potent inhibitors of CDK9 and BET proteins. In this series, compound 40 was identified as the potential lead compound with balanced activities of BRD4 (IC50 = 12.7 nM) and CDK9 (IC50 = 22.4 nM), as well as good antiproliferative activities on a small cancer cell panel. Together, the current study provided a new method for the discovery of bromodomain and kinase dual inhibitors rather than only being discovered by serendipity.
- Subjects :
- 0303 health sciences
BRD4
Drug discovery
Chemistry
Rational design
01 natural sciences
Combinatorial chemistry
0104 chemical sciences
Bromodomain
010404 medicinal & biomolecular chemistry
03 medical and health sciences
chemistry.chemical_compound
Drug Discovery
Molecular Medicine
Structure–activity relationship
Cyclin-dependent kinase 9
Pharmacophore
Lead compound
030304 developmental biology
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 63
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi...........5b67f17a908b1d784b3b6b451ce93294