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Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer
- Source :
- Cancer research, vol 77, iss 5
- Publication Year :
- 2017
- Publisher :
- eScholarship, University of California, 2017.
-
Abstract
- The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). In addition, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients. Cancer Res; 77(5); 1200–11. ©2017 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Lung Neoplasms
Oncology and Carcinogenesis
Mice, SCID
Pharmacology
SCID
Transfection
Article
Cell Line
03 medical and health sciences
T790M
Mice
0302 clinical medicine
Therapeutic index
Rare Diseases
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
medicine
Animals
Humans
Osimertinib
Oncology & Carcinogenesis
Lung cancer
Non-Small-Cell Lung
Protein Kinase Inhibitors
Lung
Cancer
Tumor
business.industry
Kinase
Carcinoma
Lung Cancer
Neurosciences
medicine.disease
Small molecule
ErbB Receptors
030104 developmental biology
Orphan Drug
Good Health and Well Being
Oncology
5.1 Pharmaceuticals
030220 oncology & carcinogenesis
Adenocarcinoma
Female
Development of treatments and therapeutic interventions
business
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Cancer research, vol 77, iss 5
- Accession number :
- edsair.doi.dedup.....f2a6e73fe71383d010407f1a14a481b0