Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer

Mu Chun Li, Mohane Selvaraj Coumar, Shu Yu Lin, Yih Shyan Lin, Guan Lin Huang, Chun Hwa Chen, Tzu Wen Lien, Yi Wen Wu, Yen Ting Chen, Ching Ping Chen, Yu Chen Huang, Kai Chia Yeh, Chen Ming Yang, Bikashita Kalita, Shiow Lin Pan, Tsu An Hsu, Teng Kuang Yeh, Chiung Tong Chen, Hsing Pang Hsieh

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2566-2588
Number of pages23
JournalJournal of Medicinal Chemistry
Volume66
Issue number4
DOIs
Publication statusPublished - Feb 2023

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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