Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential

Jun Fujimoto; Takaharu Hirayama; Yasuhiro Hirata; Yukiko Hikichi; Saomi Murai; Maki Hasegawa; Yuka Hasegawa; Kazuko Yonemori; Akito Hata; Kazunobu Aoyama; Douglas R Cary

doi:10.1016/j.bmc.2017.03.049

Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential

Bioorg Med Chem. 2017 Jun 15;25(12):3018-3033. doi: 10.1016/j.bmc.2017.03.049. Epub 2017 Mar 30.

Authors

Affiliations

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: jun.fujimoto@takeda.com.
² Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
³ Product Information Group Japan Oncology Business Unit, Takeda Pharmaceutical Co., Ltd., 12-10, Nihonbashi 2-Chome, Chuo-ku, Tokyo 103-8686, Japan.

PMID: 28392276
DOI: 10.1016/j.bmc.2017.03.049

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 IC₅₀: 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.

Keywords: CDK19; CDK8; Cyclin-dependent kinases (CDKs); DMG; MCM3; Pyridylacrylamide; RPMI8226; STAT1; SW480; Transcriptional regulation.

MeSH terms

Animals
Cell Line, Tumor
Cyclin-Dependent Kinase 8 / antagonists & inhibitors*
Cyclin-Dependent Kinase 8 / metabolism
Cyclin-Dependent Kinases / antagonists & inhibitors*
Cyclin-Dependent Kinases / metabolism
Cytochrome P-450 CYP3A / metabolism
Cytochrome P-450 CYP3A Inhibitors / chemistry*
Cytochrome P-450 CYP3A Inhibitors / pharmacokinetics
Cytochrome P-450 CYP3A Inhibitors / pharmacology
Cytochrome P-450 CYP3A Inhibitors / therapeutic use*
Female
Humans
Mice
Molecular Docking Simulation
Neoplasms / drug therapy*
Neoplasms / metabolism
Neoplasms / pathology
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*

Substances

Cytochrome P-450 CYP3A Inhibitors
Protein Kinase Inhibitors
Cytochrome P-450 CYP3A
CDK19 protein, human
Cyclin-Dependent Kinase 8
Cyclin-Dependent Kinases