DDIS-11. TTI-2341: A NOVEL ORALLY BIOAVAILABLE BRAIN-PENETRANT COVALENT EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INHIBITOR FOR TREATMENT OF GLIOBLASTOMA MULTIFORME (GBM) AND BRAIN METASTASES OF NON-SMALL CELL LUNG CANCER (NSCLC)

摘要

Aberrant EGFR activity is implicated in certain central nervous system (CNS) tumors, including GBM and brain metastases of NSCLC, which occur in almost half of NSCLC patients. Current approved EGFR inhibitors, however, have very limited efficacy against those CNS tumors due to insufficient penetration of the blood-brain barrier (BBB). Thus, there is a strong unmet medical need to develop novel EGFR inhibitors that are able to effectively access the CNS. Here we report that TTI-2341, a novel covalent orally active EGFR inhibitor, demonstrates superior brain penetration and is reasonably well tolerated in preclinical studies. TTI-2341 displays potent inhibition of wild type and mutant EGFR (including resistance-associated variants L858R and T790M) with nanomolar or lower IC50s in vitro, while exhibiting selectivity for the EGFR family of kinases. TTI-2341 strongly inhibits auto-phosphorylation of EGFR at 10nM in GBM DKMG cells. Furthermore, TTI-2341 has equal or superior anti-proliferative activity compared to the benchmark marketed covalent EGFR inhibitor afatinib among most NSCLC and CNS tumor cell lines tested. ADME studies show that TTI-2341 has 3-fold higher cell permeability and 5-fold less efflux ratio than afatinib in Caco-2 cells, and is not a substrate of PgP (Efflux < 2 in MDCK-MDR1 cells). Importantly, TTI-2341 has superior oral bioavailability (86%), 13-fold higher Kpuu (unbound drug brain-to-plasma ratio) and 6-fold higher brain exposure compared to afatinib. Results from the 7-day repeat dose toxicology study in rats demonstrate that TTI-2341 is well tolerated up to a dose level of 8 mg/kg with no prominent signs of CNS toxicity by clinical and histopathological assessments. Together, these results indicate that TTI-2341 achieves superior brain penetration compared to afatinib. Our data highlight the potential of TTI-2341 to achieve best-in-class status among covalent EGFR inhibitors for the treatment of CNS tumors.