ACS Medicinal Chemistry Letters · 2022 · 18 citations · 16 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryLead OptimizationChemical Library DesignHit-to-lead OptimizationLead Compound DesignLead DiscoveryPotency OptimizationTyrosine Kinase InhibitorsAntimitotic ActivityAntimitotic ChemotherapyAntimitotic DrugsAntimitotic TreatmentsAurora Kinase FunctionAurora Kinase InhibitionLead Compound ScreeningOptimization Of Drug-like Properties
We used mechanism-informed phenotypic screening to identify and optimize compounds that phenocopy the genetic depletion of the mitotic aurora kinase B (AURKB) kinase. After assaying nine aryl fused seven-membered lactam compounds, we identified a hit compound 6a that was subsequently optimized to five lead compounds with low nanomolar activity, represented by the lead compound 6v (19 nM). With excellent drug-like properties, these compounds reproduced the loss of function in phenotypes of AURKB and exhibited potent cytotoxic activities in various cancer cell lines. Collectively, these data support that seven-membered lactam-based analogs might be valuable for further development as a new type of antimitotic agents for the treatment of cancer.
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