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.

Die bei Reaktionen der Diazoacetylindole (I) mit den Aminoaldehydacetalen (II) in Gegenwart von Agbenzoat entstehenden Amide (III) gehen beim Erwärmen in l4%igem wäßrigem HCl (oder bei Erwärmung mit Polyphosphorsäure auf 30‐35°C) glatt in die Titelverbindungen (IV) über.

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