Products Cited in Publications Worldwide Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer

Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer

Hill, Jarvis; Jones, Robert M.; Crich, David

DOI: PMID:

Abstract

Metastases to the brain remain a significant problem in lung cancer, as treatment by most small mol. targeted therapies is severely limited by efflux transporters at the blood-brain-barrier (BBB). Here, we report the discovery of a selective, orally bioavailable, epidermal growth factor receptor (EGFR) inhibitor, 9, that exhibits high brain penetration and potent activity in osimertinib-resistant cell lines bearing L858R/C797S and exon19del/C797S EGFR resistance mutations. In vivo, 9 induced tumor regression in an intracranial patient-derived xenograft (PDX) murine model suggesting it as a potential lead for the treatment of localized and metastatic nonsmall-cell lung cancer (NSCLC) driven by activating mutant bearing EGFR. Overall, we demonstrate that an underrepresented functional group in medicinal chem., the trisubstituted hydroxylamine moiety, can be incorporated into a drug scaffold without the toxicity commonly surmised to accompany these units, all while maintaining potent biol. activity and without the mol. weight creep common to drug optimization campaigns.

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