2. Academic Validation
  3. Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer

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

  • J Med Chem. 2023 Feb 23;66(4):2566-2588. doi: 10.1021/acs.jmedchem.2c01434.
Mu-Chun Li 1 2,  Mohane Selvaraj Coumar 3,  Shu-Yu Lin 1,  Yih-Shyan Lin 1,  Guan-Lin Huang 1,  Chun-Hwa Chen 1,  Tzu-Wen Lien 1,  Yi-Wen Wu 4,  Yen-Ting Chen 1,  Ching-Ping Chen 1,  Yu-Chen Huang 1,  Kai-Chia Yeh 1,  Chen-Ming Yang 1,  Bikashita Kalita 3,  Shiow-Lin Pan 4 5,  Tsu-An Hsu 1,  Teng-Kuang Yeh 1,  Chiung-Tong Chen 1,  Hsing-Pang Hsieh 1 2 6
Affiliations

Affiliations

  • 1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
  • 2 Biomedical Translation Research Center, Academia Sinica, Taipei City 115202, Taiwan, ROC.
  • 3 Department of Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet 605014, Pondicherry, India.
  • 4 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei City 110301, Taiwan, ROC.
  • 5 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei City 110301, Taiwan, ROC.
  • 6 Department of Chemistry, National Tsing Hua University, Hsinchu City 300044, Taiwan, ROC.
PMID: 36749735 DOI: 10.1021/acs.jmedchem.2c01434
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.

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