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Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2017 Jun 15; Vol. 25 (12), pp. 3018-3033. Date of Electronic Publication: 2017 Mar 30. - Publication Year :
- 2017
-
Abstract
- In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC <subscript>50</subscript> : 2.5nM; CYP3A4 TDI: 99% compound remaining). Compound 4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of 4k (15mg/kg, bid. for 2weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Cell Line, Tumor
Cyclin-Dependent Kinase 8 metabolism
Cyclin-Dependent Kinases metabolism
Cytochrome P-450 CYP3A metabolism
Cytochrome P-450 CYP3A Inhibitors pharmacokinetics
Cytochrome P-450 CYP3A Inhibitors pharmacology
Female
Humans
Mice
Molecular Docking Simulation
Neoplasms metabolism
Neoplasms pathology
Protein Kinase Inhibitors pharmacokinetics
Protein Kinase Inhibitors pharmacology
Cyclin-Dependent Kinase 8 antagonists & inhibitors
Cyclin-Dependent Kinases antagonists & inhibitors
Cytochrome P-450 CYP3A Inhibitors chemistry
Cytochrome P-450 CYP3A Inhibitors therapeutic use
Neoplasms drug therapy
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 25
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28392276
- Full Text :
- https://doi.org/10.1016/j.bmc.2017.03.049