Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential. Issue 12 (15th June 2017)

• Record Type: Journal Article
• Authors: Fujimoto, Jun; Hirayama, Takaharu; Hirata, Yasuhiro; Hikichi, Yukiko; Murai, Saomi; Hasegawa, Maki; Hasegawa, Yuka; Yonemori, Kazuko; Hata, Akito; Aoyama, Kazunobu; Cary, Douglas R.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 12(2017)
• Page Start: 3018
• Page End: 3033
• Publication Date: 2017-06-15
• Subjects: ADME absorption, distribution, metabolism, and excretion -- AML acute myelogenous leukemia -- AUC area under the blood concentration time curve -- b.i.d. twice a day -- CDK Cyclin-dependent kinase -- CLtotal clearance -- Cmax maximum drug concentration -- CRC colorectal cancer -- CTD C-terminal domain -- DDI drug-drug interaction -- DMA N, N-dimethylacetamide -- DMAP N, N-dimethyl-4-aminopyridine -- DMG loop AspMetGlu loop -- F bioavailability -- FBS Fetal bovine serum -- GST glutathione S-transferase -- HATU O-(7-azabenzotriazol-1-yl)-N, N, N′, N′-tetramethyluronium-hexafluorophosphate -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- HOBt 1-hyfroxybenzotriazole -- HTS high-throughput screening -- INF interferon -- ICR Institute for Cancer Research -- CyJohnPhos 2-(dicyclohexylphosphino)biphenyl -- MCM3 mini-chromosome maintenance 3 protein -- mCPBA m-chloroperoxybenzoic acid -- MED mediator complex -- MRT mean residence time -- ODS octadecyl silyl -- PBS-T phosphate buffered saline with Tween 20 -- PD pharmacodynamic -- PDB protein data bank -- PK pharmacokinetic -- q.d. once a day -- RNAP RNA polymerase -- rt room temperature -- SBDD structure based drug design -- SPhos dicyclohexyl(2′, 6′-dimethoxy-[1, 1′-biphenyl]-2-yl)phosphine -- STAT signal transducers (transduction) and activator of transcription -- TR-FRET time-resolved fluorescence resonance energy transfer -- Vdss steady state volume of distribution -- EDC water soluble carbodiimide (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide) -- XPhos 2-dicyclohexylphosphino-2′, 4′, 6′-triisopropylbiphenyl; CDK8 -- CDK19 -- Cyclin-dependent kinases (CDKs) -- Transcriptional regulation -- STAT1 -- MCM3 -- RPMI8226 -- SW480 -- DMG -- Pyridylacrylamide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.03.049
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 compound4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC50 : 2.5 nM; CYP3A4 TDI: 99% compound remaining). Compound4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of4k (15 mg/kg, bid. for 2 weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model.