1. Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer
- Author
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Sang-Yeob Kim, Paresh Devidas Salgaonkar, Trever G. Bivona, Yun Jung Choi, Chang-Min Choi, Jaekyoo Lee, Jin Kyung Rho, Byung-Chul Suh, Jae Cheol Lee, In Young Lee, Dong Sik Jung, Chang Hoon Ha, Jeong Kon Kim, Jong Sung Koh, Jae Young Hur, Ho-Juhn Song, Joon Seon Song, Young Hoon Sung, Dong-Cheol Woo, Cheol Hyeon Kim, Joo Yong Lee, Woo Sung Kim, In-Jeoung Baek, Jaesang Lee, and Jungmi Lee
- 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 - 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.
- Published
- 2017