N-(1-Benzyl-3,5-dimethyl-1 H-pyrazol-4-yl)benzamides: Antiproliferative Activity and Effects on mTORC1 and Autophagy

  • ACS Med Chem Lett. 2016 Nov 28;8(1):90-95. doi: 10.1021/acsmedchemlett.6b00392.
Teng Ai  1 ,  Rose Willett  2 ,  Jessica Williams  1 ,  Rui Ding  1 ,  Daniel J Wilson  1 ,  Jiashu Xie  1 ,  Do-Hyung Kim  3 ,  Rosa Puertollano  2 ,  Liqiang Chen  1
Affiliations
  • 1. Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
  • 2. Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
  • 3. Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota , Minneapolis, Minnesota 55455, United States.
PMID: 28105281 DOI: 10.1021/acsmedchemlett.6b00392
Abstract

Guided by antiproliferative activity in MIA PaCa-2 cells, we have performed preliminary structure-activity relationship studies on N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides. Two selected compounds showed submicromolar antiproliferative activity and good metabolic stability. Both compounds reduced mTORC1 activity and increased Autophagy at the basal level. In addition, they disrupted autophagic flux by interfering with mTORC1 reactivation and clearance of LC3-II under starvation/refeed conditions, as evidenced by accumulation of LC3-II and abnormal LC3 labeled punctae. Therefore, N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides may represent a new class of Autophagy modulators that possesses potent Anticancer activity and potentially a novel mechanism of action.

Keywords
Autophagy; anticancer agents; autophagy modulator; mTOR; pancreatic cancer.