Glioblastoma (GBM) is the most common and most aggressive malignant primary brain tumor in adults, accounting for about 50% of all functional tissue brain tumor cases and 20% of all intracranial tumors. Deregulated ErbB signaling is associated with the development of GBM, of which approximately 45% have EGFR amplification. A tumor specific and constitutively activated mutant, EGFRvIII is often co-expressed with amplified EGFR. Unfortunately, small molecule ErbB inhibitors used to date have poor CNS penetration, and thus failed clinically against GBM.Our strategy to design blood-brain-barrier (BBB) penetrating ErbB inhibitors involved physicochemical property calculation, activity screening, and rapid pharmacokinetic (PK) profiling. This effort led to the discovery of NT113, a potent, irreversible pan-ErbB inhibitor that has excellent CNS exposure in rats and mice. NT113 completely suppressed tumor growth for a two-week period of NT113 administration and significantly prolonged the lifespan of treated mice in an EGFRvIII mutant GBM xenograft model. In a second intracranial xenograft experiment involving GBM cells with amplification of wild-type EGFR, NT113 significantly outperformed both erlotinib and lapatinib, with each therapeutic administered at its daily MTD for athymic mice. In addition, NT113 also exhibited potent anti-cancer activity in subcutaneous xenograft models with either HER2 over-expression or T790M/L858R EGFR mutation. Therefore, it may also find applications in treating cancer patients with brain metastases from extra-cranial primary tumors.

Identification and preclinical evaluation of NT113, a novel pan-ErbB kinase inhibitor for the treatment of glioblastoma (GBM)

247th National Meeting (2014)

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