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Journal article
Development of a Potent Brain-Penetrant EGFR Tyrosine Kinase Inhibitor against Malignant Brain Tumors
ACS medicinal chemistry letters, v 11(10), pp 1799-1809
08 Oct 2020
PMID: 33062157
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The epidermal growth factor receptor (EGFR) is genetically altered in nearly 60% of glioblastoma tumors; however, tyrosine kinase inhibitors (TKIs) against EGFR have failed to show efficacy for patients with these lethal brain tumors. This failure is attributed to the inability of clinically tested EGFR TKIs to cross the blood-brain barrier (BBB) and achieve adequate pharmacological levels to inhibit various oncogenic forms of EGFR that drive glioblastoma. Through SAR analysis, we developed compound 5 (JCN037) from an anilinoquinazoline scaffold by ring fusion of the 6,7-dialkoxy groups to reduce the number of rotatable bonds and polar surface area and by introduction of an orthofluorine and meta-bromine on the aniline ring for improved potency and BBB penetration. Relative to the conventional EGFR TKIs erlotinib and lapatinib, JCN037 displayed potent activity against EGFR amplified/mutant patient-derived cell cultures, significant BBB penetration (2:1 brain-to-plasma ratio), and superior efficacy in an EGFR-driven orthotopic glioblastoma xenograft model.
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Details
- Title
- Development of a Potent Brain-Penetrant EGFR Tyrosine Kinase Inhibitor against Malignant Brain Tumors
- Creators
- Jonathan E. Tsang - Semel Institute for Neuroscience and Human BehaviorLorenz M. Urner - Semel Institute for Neuroscience and Human BehaviorGyudong Kim - Semel Institute for Neuroscience and Human BehaviorKingsley Chow - Semel Institute for Neuroscience and Human BehaviorLynn Baufeld - Semel Institute for Neuroscience and Human BehaviorKym Faull - Semel Institute for Neuroscience and Human BehaviorTimothy F. Cloughesy - Semel Institute for Neuroscience and Human BehaviorPeter M. Clark - Semel Institute for Neuroscience and Human BehaviorMichael E. Jung - Semel Institute for Neuroscience and Human BehaviorDavid A. Nathanson - Semel Institute for Neuroscience and Human Behavior
- Publication Details
- ACS medicinal chemistry letters, v 11(10), pp 1799-1809
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 11
- Grant note
- Ziering Family Foundation Uncle Kory Foundation B Hasso Family Foundation Margaret M Bloomfield/Hunter Family Foundation Art of the Brain Sharpe/NBTS Grant P50 CA211015; R01 CA213133 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Spiegelman Family Foundation in Memory of Barry Spiegelman
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems; Drexel University
- Web of Science ID
- WOS:000580567800004
- Scopus ID
- 2-s2.0-85089266645
- Other Identifier
- 991019356497204721
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- Web of Science research areas
- Chemistry, Medicinal