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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.

EGFR mutations identified in glioblastomas (GBM) occur nearly exclusively at the allosteric extracellular domain (ECD) and constitutively activate oncogenic signaling. Despite wide success in treating tumors expressing EGFR catalytic site mutants, no drug has demonstrated clinical utility against tumors expressing the extracellular domain EGFR mutants. We demonstrate that the family of ECD mutations are not only co-expressed in GBM, but that they all activate the oncogene through a similar disulfide bond-mediated receptor dimerization mechanism. This dimerization occurs independent of ligands and renders the Locked-dimer (LoDi)-EGFR insensitive to agents that target the EGFR kinase domain mutants in NSCLC. The kinase conformation induced by these ECD mutations seen in glioblastomas is both oncogenic and altered from kinase domain mutations, thus necessitating a new approach to targeting. By screening against cells expressing LoDi-EGFR mutants, we have identified the first inhibitors that potently and selectively target LoDi-EGFR mutants versus both canonical active site oncogenic mutants and wild type EGFR. Through an optimization effort, we have identified a novel family of potent and selective LoDi-EGFR mutant inhibitors that effectively penetrate the blood brain barrier (BBB) following oral dosing in preclinical studies. A leading exemplar, BDTX-GBM-001, inhibits the 5 major LoDi-EGFR mutants expressed in GBM with antiproliferative potency of ~10 nM while showing favorable selectivity versus the human kinome. When dosed orally in the intracranial GBM6 patient derived xenograft model at 50, 30, and 15 mg/kg, a dose responsive decrease in tumor growth, as well as a statistically significant increase in survival, were observed. These data support the continued evaluation of rationally designed BBB penetrant inhibitors selectively targeting the common LoDi-EGFR mutants and enable the first chance to fully test the clinical hypothesis of EGFR driver mutants in GBM.

We asked young scientists this question: What is your New Year's resolution for your field? Describe one thing that your field's research community could do better in the coming year . We received responses from scientists around the world representing a variety of fields. Excerpts of their