title: N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides: Antiproliferative Activity and Effects on mTORC1 and Autophagy.
abstract: Guided by antiproliferative activity in MIA PaCa-2 cells, we have performed preliminary structure-activity relationship studies onN-(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.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Teng
authors.initials: T
authors.lastname: Ai
authors.affiliation: Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Rose
authors.initials: R
authors.lastname: Willett
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Williams
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Ding
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Jiashu
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Do-Hyung
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Rosa
authors.initials: R
authors.lastname: Puertollano
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
keywords: Autophagy; anticancer agents; autophagy modulator; mTOR; pancreatic cancer