Identification and preliminary structure–activity relationship of brain‐penetrant quinoxaline‐based compounds with in vitro anti‐glioblastoma activity.

A central nervous system (CNS)‐oriented compound collection was screened to find hit compounds for human glioblastoma T98G cell growth inhibition. A series of quinoxaline‐based derivatives were identified as hit compounds having one‐ to two‐digit micromolar GI50 values. Anti‐glioblastoma activity was improved in structure–activity relationship studies varying the substituents on the quinoxaline ring system, resulting in the discovery of four compounds exhibiting sub‐micromolar GI50 values. The potentials of the four compounds to induce apoptosis were confirmed by annexin V staining assay. The development potential of the four compounds as CNS drug leads was evaluated by in vitro MDR‐MDCK cell permeability and in vivo brain disposition in mice. The mouse pharmacokinetic and kinome profiling studies for compound 10g, which showed high brain‐penetrating ability, revealed that the compound is orally bioavailable and inhibits the kinase activities of anaplastic lymphoma kinase (ALK) and Erb‐B2 receptor tyrosine kinase (ERBB3). [ABSTRACT FROM AUTHOR]