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 GI(50) 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 GI(50) 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).