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We reported a novel, high CNS (central nervous system) penetrance pan-ERBB inhibitor, NT-113, for anti-glioma therapy. Using five intracranial glioblastoma (GBM) models, we found that NT-113 significantly suppresses growth of tumors overexpressing wild-type EGFR or the EGFRvIII mutant, resulting in improved animal survival. NT-113 inhibits ERBB activity at low nanomolar (u003c 5 nM) concentrations, and suppresses its downstream signaling through Akt, leading to reduced cell proliferation and increased apoptosis. When compared with previous generations of EGFR small tyrosine kinase inhibitors (TKIs), erlotinib and lapatanib, NT-113 shows the most substantial effect on tumor growth inhibition and animal survival. The superior anti-glioma activity of NT-113 can be explained by broader spectrum of ERBB inhibition, efficient brain penetrance, and superior tumor uptake. Our data support clinical investigation of NT-113 in glioma over-expressing wild type or vIII forms of EGFR.

NT-113, A Novel, High CNS Penetrance pan-ERBB Inhibitor for Glioma Therapy