title: Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer.
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.
authors.affiliation: 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.|Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.|Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Rho
authors.affiliation: Genosco, Cambridge, Massachusetts.
authors.forename: In Yong
authors.initials: IY
authors.lastname: Lee
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.|Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Yun Jung
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.|Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Choi
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.|Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Hur
authors.affiliation: Genosco, Cambridge, Massachusetts.
authors.forename: Jong Sung
authors.initials: JS
authors.lastname: Koh
authors.affiliation: Genosco, Cambridge, Massachusetts.
authors.forename: Jaekyoo
authors.initials: J
authors.lastname: Lee
authors.affiliation: Genosco, Cambridge, Massachusetts.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Suh
authors.affiliation: Genosco, Cambridge, Massachusetts.
authors.forename: Ho-Juhn
authors.initials: HJ
authors.lastname: Song
authors.affiliation: Genosco, Cambridge, Massachusetts.
authors.forename: Paresh
authors.initials: P
authors.lastname: Salgaonkar
authors.affiliation: Genosco, Cambridge, Massachusetts.
authors.forename: Jungmi
authors.initials: J
authors.lastname: Lee
authors.affiliation: Oscotec Inc., Seongnam, Korea.
authors.forename: Jaesang
authors.initials: J
authors.lastname: Lee
authors.affiliation: Oscotec Inc., Seongnam, Korea.
authors.forename: Dong Sik
authors.initials: DS
authors.lastname: Jung
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.|Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Sang-Yeob
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.|Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Dong-Cheol
authors.initials: DC
authors.lastname: Woo
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.|Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: In-Jeoung
authors.initials: IJ
authors.lastname: Baek
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.|Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.|Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Ha
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.|Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Sung
authors.affiliation: Department of Radiology, Research Institute of Radiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Jeong Kon
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Woo Sung
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Joon Seon
authors.initials: JS
authors.lastname: Song
authors.affiliation: Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea.
authors.forename: Cheol Hyeon
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California. trever.bivona@ucsf.edu jkrho@amc.seoul.kr jclee@amc.seoul.kr.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Trever G
authors.initials: TG
authors.lastname: Bivona
authors.affiliation: 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.
authors.forename: Jae Cheol
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014162:Transfection
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors