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Cancer Res. 2017 Mar 1;77(5):1200-1211. doi: 10.1158/0008-5472.CAN-16-2432. Epub 2017 Jan 12.

Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer.

Author information

1
Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea. trever.bivona@ucsf.edu jkrho@amc.seoul.kr jclee@amc.seoul.kr.
2
Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
3
Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
4
Genosco, Cambridge, Massachusetts.
5
Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
6
Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
7
Oscotec Inc., Seongnam, Korea.
8
Department of Radiology, Research Institute of Radiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
9
Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
10
Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea.
11
Department of Medicine, University of California San Francisco, San Francisco, California. trever.bivona@ucsf.edu jkrho@amc.seoul.kr jclee@amc.seoul.kr.
12
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
13
Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea. trever.bivona@ucsf.edu jkrho@amc.seoul.kr jclee@amc.seoul.kr.

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.

PMID:
28082405
PMCID:
PMC5334209
DOI:
10.1158/0008-5472.CAN-16-2432
[Indexed for MEDLINE]
Free PMC Article

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