Oncogenic EGFR mutations occur in approximately 50% of glioblastomas (GBM) and largely reside in the extracellular domain. Prior attempts to reposition current generation EGFR inhibitors to treat GBM likely failed due to poor brain penetration and an inability to potently target the full spectrum of oncogenic mutations. As EGFR oncogenic mutations are found to be co-expressed in many GBMs, it is important that an inhibitor be broadly active against the entire family of relevant EGFR mutants. Additionally, a successful inhibitor would require a pharmacokinetic (PK) profile that allows for sufficient penetration of the blood brain barrier to elicit robust target engagement of the brain tumor. Using these design principles, we designed a series of highly potent molecules exemplified by BDTX-507. This molecule is an irreversible inhibitor of EGFR with antiproliferative IC50's less than 10 nM against the spectrum of GBM-relevant EGFR mutations. PK/PD studies demonstrated sustained pERK suppression exceeding 24 hours following a single QD dose. Furthermore, when dosed in GBM xenografts, including an intracranial Viii PDX (GBM6), robust tumor regressions and improved survival were observed. Emerging from this series were two advanced compounds, BDTX-700 and BDTX-1535, which also demonstrated potent inhibition of the GBM EGFR spectrum, selectivity v. wild-type EGFR, and an excellent CNS PK profile. BDTX-1535 is currently being evaluated in IND-enabling studies for future clinical evaluation in GBM patients.

Citation Format: Matthew O'Connor, Matt Lucas, Darlene Romashko, Sara Rasmussen, Tai-An Lin, Nigel Waters, Raffaele Fiorenza, Iwona Wrona, Deborah Chen, Theodore Nicolaides, David R. Raleigh, Tomoko Ozawa, George Trainor, Luca Arista, Alexander Flohr, Giorgio Ottaviani, Chris Roberts, Elizabeth Buck. CNS penetrant, irreversible inhibitors potently inhibit the family of allosteric oncogenic EGFR mutants expressed in GBM and demonstrate efficacy in patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB140.