@article{8c5b0ec29859438c9b79def7372229b6,
title = "Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer",
abstract = "The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the (S)-2-phenylglycinol moiety of 12 with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead 52 shows 8-fold selective inhibition of H1975 (EGFRL858R/T790M overexpressing) cancer cells over A431 (EGFRWT overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by 52. Notably, 52 displayed in vivo antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration (F = 27%), respectively. With an extraordinary kinome selectivity (S(10) score of 0.017), 52 undergoes detailed preclinical development.",
author = "Li, {Mu Chun} and Coumar, {Mohane Selvaraj} and Lin, {Shu Yu} and Lin, {Yih Shyan} and Huang, {Guan Lin} and Chen, {Chun Hwa} and Lien, {Tzu Wen} and Wu, {Yi Wen} and Chen, {Yen Ting} and Chen, {Ching Ping} and Huang, {Yu Chen} and Yeh, {Kai Chia} and Yang, {Chen Ming} and Bikashita Kalita and Pan, {Shiow Lin} and Hsu, {Tsu An} and Yeh, {Teng Kuang} and Chen, {Chiung Tong} and Hsieh, {Hsing Pang}",
note = "Funding Information: Financial support from the National Health Research Institutes, Taiwan; the Biomedical Translation Research Center, Academia Sinica, Taiwan; and the National Science and Technology Council, Taiwan (MOST-111-2113-M-400-003) is acknowledged. This work is also financially supported by the Center of Applied Nanomedicine, National Cheng Kung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. The authors also thank Shih-An Yang, Pei-Yi Chen, Fu-Ming Kuo, Dr. Ka-Shu Fung, Hsu-Yi Sun, Dr. Hui-Yi Shiao, and Dr. Chang-Ying Chu (National Health Research Institutes) for their support of the synthesis; Dr. Hsin-Ru Wu, Instruments Center at National Tsing Hua University, for her help in obtaining mass spectral data (MOST 110-2731-M-007-001); and Dr. Richard Guy for help with English editing. Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society.",
year = "2023",
month = feb,
doi = "10.1021/acs.jmedchem.2c01434",
language = "English",
volume = "66",
pages = "2566--2588",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "4",
}
