title: Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential.
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.
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Fujimoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Hirayama
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Product Information Group Japan Oncology Business Unit, Takeda Pharmaceutical Co., Ltd., 12-10, Nihonbashi 2-Chome, Chuo-ku, Tokyo 103-8686, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hikichi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Saomi
authors.initials: S
authors.lastname: Murai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Yonemori
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Hata
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Aoyama
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Cary
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056850:Cyclin-Dependent Kinase 8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D047428:Protein Kinase Inhibitors; D051544:Cytochrome P-450 CYP3A; C584437:CDK19 protein, human; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases
keywords: CDK19; CDK8; Cyclin-dependent kinases (CDKs); DMG; MCM3; Pyridylacrylamide; RPMI8226; STAT1; SW480; Transcriptional regulation