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Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer
Jarvis Hill1,2, Robert M Jones3, David Crich1,2,4
1Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 250 West Green Street, Athens, Georgia 30602, United States.
Abstract:
Metastases to the brain remain a significant problem in lung cancer, as treatment by most small-molecule 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 non-small-cell lung cancer (NSCLC) driven by activating mutant bearing EGFR. Overall, we demonstrate that an underrepresented functional group in medicinal chemistry, the trisubstituted hydroxylamine moiety, can be incorporated into a drug scaffold without the toxicity commonly surmised to accompany these units, all while maintaining potent biological activity and without the molecular weight creep common to drug optimization campaigns.
Insights
A new drug candidate, compound 9, effectively targets brain metastases in lung cancer by penetrating the blood-brain barrier. It shows promise for treating non-small-cell lung cancer with specific epidermal growth factor receptor mutations.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Brain metastases are a major challenge in lung cancer treatment.
- Existing therapies are limited by the blood-brain barrier (BBB) and drug efflux transporters.
- Epidermal growth factor receptor (EGFR) mutations drive non-small-cell lung cancer (NSCLC) and resistance to targeted therapies.
Purpose of the Study:
- To discover and characterize a novel, brain-penetrant EGFR inhibitor for treating lung cancer brain metastases.
- To evaluate the efficacy of the novel inhibitor in preclinical models of EGFR-mutant NSCLC.
- To explore the utility of trisubstituted hydroxylamine moieties in drug design.
Main Methods:
- Discovery and synthesis of a selective, orally bioavailable EGFR inhibitor (compound 9).
- Assessment of compound 9's activity in osimertinib-resistant cell lines with specific EGFR mutations (L858R/C797S, exon19del/C797S).
- Evaluation of compound 9's in vivo efficacy in an intracranial patient-derived xenograft (PDX) murine model.
Main Results:
- Compound 9 demonstrated high brain penetration and potent activity against EGFR-mutant, osimertinib-resistant NSCLC cell lines.
- In vivo studies showed that compound 9 induced tumor regression in an intracranial PDX model.
- The trisubstituted hydroxylamine moiety was successfully incorporated without significant toxicity or molecular weight increase.
Conclusions:
- Compound 9 is a promising lead candidate for treating EGFR-mutant NSCLC, including brain metastases.
- This study validates the use of trisubstituted hydroxylamines in developing potent and brain-penetrant drug molecules.
- Targeting brain metastases in NSCLC can be achieved with novel, BBB-penetrant EGFR inhibitors.
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