N-(1-Benzyl-3,5-dimethyl‑1H‑pyrazol-4-yl)benzamides: Antiproliferative activity and effects on mTORC1 and autophagy

Teng Ai, Rose Willett, Jessica Williams, Rui Ding, Daniel J. Wilson, Jiashu Xie, Do Hyung Kim, Rosa Puertollano, Liqiang Chen

Research output: Contribution to journalArticle

4 Citations (Scopus)

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-(1benzyl-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.

Original languageEnglish (US)
Pages (from-to)90-95
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2017

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Benzamides
Autophagy
Starvation
Modulators
Fluxes
mechanistic target of rapamycin complex 1

Keywords

  • Anticancer agents
  • Autophagy
  • Autophagy modulator
  • MTOR
  • Pancreatic cancer

Cite this

N-(1-Benzyl-3,5-dimethyl‑1H‑pyrazol-4-yl)benzamides : Antiproliferative activity and effects on mTORC1 and autophagy. / Ai, Teng; Willett, Rose; Williams, Jessica; Ding, Rui; Wilson, Daniel J.; Xie, Jiashu; Kim, Do Hyung; Puertollano, Rosa; Chen, Liqiang.

In: ACS Medicinal Chemistry Letters, Vol. 8, No. 1, 01.01.2017, p. 90-95.

Research output: Contribution to journalArticle

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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-(1benzyl-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.",
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AU - Ai, Teng

AU - Willett, Rose

AU - Williams, Jessica

AU - Ding, Rui

AU - Wilson, Daniel J.

AU - Xie, Jiashu

AU - Kim, Do Hyung

AU - Puertollano, Rosa

AU - Chen, Liqiang

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AB - 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-(1benzyl-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.

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