A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics

Abstract

Senexins are potent and selective quinazoline inhibitors of CDK8/19 Mediator kinases. To improve their potency and metabolic stability, quinoline-based derivatives were designed through a structure-guided strategy based on the simulated drug–target docking model of Senexin A and Senexin B. A library of quinoline-Senexin derivatives was synthesized to explore the structure–activity relationship (SAR). An optimized compound 20a (Senexin C) exhibits potent CDK8/19 inhibitory activity with high selectivity. Senexin C is more metabolically stable and provides a more sustained inhibition of CDK8/19-dependent cellular gene expression when compared with the prototype inhibitor Senexin B. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) evaluation using a novel tumor-based PD assay showed good oral bioavailability of Senexin C with a strong tumor-enrichment PK profile and tumor-PD marker responses. Senexin C inhibits MV4-11 leukemia growth in a systemic in vivo model with good tolerability.

Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo

“…We have tested the interactions between two anti-HER2 drugs, the small-molecule kinase inhibitor lapatinib and the monoclonal antibody trastuzumab, and two chemically distinct selective CDK8/19i, senexin B ( 10 ) and SNX631 (also known as 15u) ( 25 ). SI Appendix , Table S2 provides the chemical formulas and compares the activities of senexin B and SNX631 in a battery of cell-free and cell-based assays for CDK8/19 inhibition ( 26 ). SNX631 was 6 to 10 times more potent than senexin B in all the assays except for the DiscoverX active-site–dependent competition binding assay.…”

Mediator kinase inhibition reverses castration resistance of advanced prostate cancer

“…Although systemic toxicity was reported for two CDK8/19i ( 23 ), it was subsequently found to be due to off-target effects of these compounds ( 24 ). Several CDK8/19i have reached clinical trials in solid tumors and leukemias (ClinicalTrials.gov NCT03065010, NCT04021368, NCT05052255, NCT05300438) ( 25 ).…”

Cu-Catalyzed Decarboxylative Annulation of N-Phenylglycines with Maleimides: Synthesis of 1H-Pyrrolo[3,4-c]quinoline-1,3(2H)-diones

“…As derivatives of quinolines, 1 H -pyrrolo­[3,4- c ]­quinoline-1,3­(2 H )-diones (PQLs), which include caspase-3 inhibitors (compound A), PI3K/mTOR inhibitors (BEZ235 and LY3023414), CDK8/19 mediator kinase inhibitors, and GLI1 inhibitors, have demonstrated excellent preclinical antitumor activities. Therefore, PQLs have attracted significant attention as potential drug candidates because of their unique and broad biological activities, including antiviral and anti-inflammatory activities .…”

“…However, several new methods were recently reported, including the palladiumcatalyzed intermolecular electrocyclizations of 2-vinylarylimines, 10 [4 + 2] or [3 + 2 + 1] reactions of Narylmethanimines with vinylene carbonate, 11 [3 + 3] annulations between anilines and CF 3 -ynones, 12 annulations of 2-vinylanilines with sulfoxonium ylides or gem-dichloroalkenes, 13 annulations of 2-ethynylanilines with glyoxals, 14 cyclizations of o-aminoaceto-phenone derivatives with alkynes/ alkenes, 15 and others. 16−18 As derivatives of quinolines, 1H-pyrrolo [3,4-c]quinoline-1,3(2H)-diones (PQLs), which include caspase-3 inhibitors (compound A), 19 PI3K/mTOR inhibitors (BEZ235 and LY3023414), 20 CDK8/19 mediator kinase inhibitors, 21 and GLI1 inhibitors, 22 have demonstrated excellent preclinical antitumor activities. Therefore, PQLs have attracted significant attention as potential drug candidates because of their unique and broad biological activities, including antiviral and antiinflammatory activities.…”