Dr. Yang, Pan-Chyr 's publons link picture

Dr. Yang, Pan-Chyr

Joint Appointment Research Fellow
Academician, Academia Sinica
  • 02-27899149 (Lab) (Room No: 511)
  • 02-27858594 (Fax)

  • Cell and Molecular Biology
  • Cancer genomics

Education and Positions:
  • M.D., Ph.D. National Taiwan University

Highlight Detail

Suppression of Drug-Resistant Non-Small-Cell Lung Cancer with Inhibitors Targeting Minichromosomal Maintenance Protein

Dr. Yang, Pan-Chyr
Journal of Medicinal Chemistry, Mar 26, 2020

Drug resistance has been a major threat in cancer therapies that necessitates the development of new strategies to overcome this problem. We report here a cell-based high-throughput screen of a library containing two-million molecules for the compounds that inhibit the proliferation of non-small-cell lung cancer (NSCLC). Through the process of phenotypic screening, target deconvolution, and structure–activity relationship (SAR) analysis, a compound of furanonaphthoquinone-based small molecule, AS4583, was identified that exhibited potent activity in tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant NSCLC cells (IC50 = 77 nM) and in xenograft mice. The mechanistic studies revealed that AS4583 inhibited cell-cycle progression and reduced DNA replication by disrupting the formation of the minichromosomal maintenance protein (MCM) complex. Subsequent SAR study of AS4583 gave compound RJ-LC-07-48 which exhibited greater potency in drug-resistant NSCLC cells (IC50 = 17 nM) and in mice with H1975 xenograft tumor.