학술논문
Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer
Document Type
article
Author
Rho, Jin Kyung; Lee, In Yong; Choi, Yun Jung; Choi, Chang-Min; Hur, Jae-Young; Koh, Jong Sung; Lee, Jaekyoo; Suh, Byung-Chul; Song, Ho-Juhn; Salgaonkar, Paresh; Lee, Jungmi; Lee, Jaesang; Jung, Dong Sik; Kim, Sang-Yeob; Woo, Dong-Cheol; Baek, In-Jeoung; Lee, Joo-Yong; Ha, Chang Hoon; Sung, Young Hoon; Kim, Jeong Kon; Kim, Woo Sung; Song, Joon Seon; Kim, Cheol Hyeon; Bivona, Trever G; Lee, Jae Cheol
Source
Cancer Research. 77(5)
Subject
Language
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.