Design and synthesis of selective CDK8/19 dual inhibitors: Discovery of 4, 5-dihydrothieno[3′, 4′:3, 4]benzo[1, 2-d]isothiazole derivatives. Issue 8 (15th April 2017)

• Record Type: Journal Article
• Authors: Ono, Koji; Banno, Hiroshi; Okaniwa, Masanori; Hirayama, Takaharu; Iwamura, Naoki; 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 8(2017)
• Page Start: 2336
• Page End: 2350
• Publication Date: 2017-04-15
• Subjects: CDK8 -- CDK19 -- Cyclin-dependent kinases (CDKs) -- Transcriptional regulation -- STAT1 -- RPMI8226 -- SW480 -- DMG -- 4, 5-Dihydrothieno[3′, 4′:3, 4]benzo[1, 2-d]isothiazole; 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.2017.02.038
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: To develop a novel series of CDK8/19 dual inhibitors, we employed structure-based drug design using docking models based on a library compound, 4, 5-dihydroimidazolo[3′, 4′:3, 4]benzo[1, 2- d ]isothiazole16 bound to CDK8. We designed various [5, 6, 5]-fused tricyclic scaffolds bearing a carboxamide group to maintain predicted interactions with the backbone CO and NH of Ala100 in the CDK8 kinase hinge region. We found that 4, 5-dihydrothieno[3′, 4′:3, 4]benzo[1, 2- d ]isothiazole derivative29a showed particularly potent enzymatic inhibitory activity in both CDK8/19 (CDK8 IC50 : 0.76 nM, CDK19 IC50 : 1.7 nM). To improve the physicochemical properties and kinase selectivity of this compound, we introduced a substituted 3-pyridyloxy group into the scaffold 8-position. The resulting optimized compound52h showed excellent in vitro potency (CDK8 IC50 : 0.46 nM, CDK19 IC50 : 0.99 nM), physicochemical properties, and kinase selectivity (only 5 kinases showed <35% unbound fraction at 300 nM. CDK19: 4.6%, CDK8: 8.3%, HASPIN: 23%, DYRK1B: 27%, HIP1: 32%). Based on a docking model of52h bound to CDK8, we could explain the highly specific kinase activity profile found for this compound, based on the interaction of the pyridyl group of52h interacting with Met174 of the CDK8 DMG activation loop. In vitro pharmacological evaluation of52h revealed potent suppression of phosphorylated STAT1 in various cancer cells. The high oral bioavailability found for this compound enabled in vivo studies, in which we demonstrated a mechanism-based in vivo PD effect as well as tumor growth suppression in an RPMI8226 human hematopoietic and lymphoid xenograft model in mouse [T/C: −1% (2.5 mg/kg, qd)].