Discovery of Potent Inhibitors against P-Glycoprotein-Mediated Multidrug Resistance Aided by Late-Stage Functionalization of a 2-(4-(Pyridin-2-yl)phenoxy)pyridine Analogue

  • J Med Chem. 2020 May 28;63(10):5458-5476. doi: 10.1021/acs.jmedchem.0c00337.
Yao Ma  1 ,  Dawei Yin  2 ,  Jingjia Ye  2 ,  Xiduan Wei  2 ,  Yameng Pei  2 ,  Xueyuan Li  2 ,  Guangxu Si  2 ,  Xuan-Yu Chen  3  4 ,  Zhe-Sheng Chen  3 ,  Yi Dong  1 ,  Feng Zou  5 ,  Wei Shi  5 ,  Qianqian Qiu  5 ,  Hai Qian  5 ,  Gang Liu  2
Affiliations
  • 1. Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nanwei Road, Xicheng District, Beijing 100050, P. R. China.
  • 2. School of Pharmaceutical Sciences, Tsinghua University, Haidian District, Beijing 100084, P. R. China.
  • 3. College of Pharmacy and Health Science, St. John's University, Queens, New York, New York 11439, United States.
  • 4. College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, China.
  • 5. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. China.
PMID: 32329342 DOI: 10.1021/acs.jmedchem.0c00337
Abstract

SIS3 is a specific inhibitor of SMAD3 that inhibits the TGFβ1-induced phosphorylation of SMAD3. In this article, a variety of SIS3 derivatives were designed and synthesized to discover potential inhibitors against P-glycoprotein-mediated multidrug resistance aided by late-stage functionalization of a 2-(4-(pyridin-2-yl)phenoxy)pyridine analogue. A novel class of potent P-gp reversal agents were investigated, and a lead compound 37 was identified as a potent P-gp reversal agent with strong bioactivity and outstanding affinity for P-gp.