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

doi:10.1021/acsmedchemlett.6b00392

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 journal › Article › peer-review

12 Scopus citations

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 language	English (US)
Pages (from-to)	90-95
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	8
Issue number	1
DOIs	https://doi.org/10.1021/acsmedchemlett.6b00392
State	Published - Jan 12 2017

Bibliographical note

Publisher Copyright:
© 2016 American Chemical Society.

Keywords

Anticancer agents
Autophagy
Autophagy modulator
MTOR
Pancreatic cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsmedchemlett.6b00392

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5238460

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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 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.",

keywords = "Anticancer agents, Autophagy, Autophagy modulator, MTOR, Pancreatic cancer",

author = "Teng Ai and Rose Willett and Jessica Williams and Rui Ding and Wilson, {Daniel J.} and Jiashu Xie and Kim, {Do Hyung} and Rosa Puertollano and Liqiang Chen",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2017",

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doi = "10.1021/acsmedchemlett.6b00392",

language = "English (US)",

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T2 - Antiproliferative activity and effects on mTORC1 and autophagy

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

PY - 2017/1/12

Y1 - 2017/1/12

N2 - 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.

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.

KW - Anticancer agents

KW - Autophagy

KW - Autophagy modulator

KW - MTOR

KW - Pancreatic cancer

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

Abstract

Bibliographical note

Keywords

UN SDGs

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