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

8 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

Funding Information:
This work was supported by the Center for Drug Design in the Academic Health Center of the University of Minnesota (to L. C.). R.W. and R.P. were supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). D.-H.K. was supported by the National Institute of General Medical Sciences (NIGMS) (R01GM097057). We thank Dr. Huaqing Cui for the initial synthesis of compound 1.

Keywords

Anticancer agents
Autophagy
Autophagy modulator
MTOR
Pancreatic cancer

Access

10.1021/acsmedchemlett.6b00392

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

Fingerprint Dive into the research topics of 'N-(1-Benzyl-3,5-dimethyl‑1H‑pyrazol-4-yl)benzamides: Antiproliferative activity and effects on mTORC1 and autophagy'. Together they form a unique fingerprint.

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, 12.01.2017, p. 90-95.

Research output: Contribution to journal › Article › peer-review

@article{fda5da0d590e4302abd6078fea097e3b,

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 = "Funding Information: This work was supported by the Center for Drug Design in the Academic Health Center of the University of Minnesota (to L. C.). R.W. and R.P. were supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). D.-H.K. was supported by the National Institute of General Medical Sciences (NIGMS) (R01GM097057). We thank Dr. Huaqing Cui for the initial synthesis of compound 1.",

year = "2017",

month = jan,

day = "12",

doi = "10.1021/acsmedchemlett.6b00392",

language = "English (US)",

volume = "8",

pages = "90--95",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "1",

}

TY - JOUR

T1 - N-(1-Benzyl-3,5-dimethyl‑1H‑pyrazol-4-yl)benzamides

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

N1 - Funding Information: This work was supported by the Center for Drug Design in the Academic Health Center of the University of Minnesota (to L. C.). R.W. and R.P. were supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). D.-H.K. was supported by the National Institute of General Medical Sciences (NIGMS) (R01GM097057). We thank Dr. Huaqing Cui for the initial synthesis of compound 1.

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

UR - http://www.scopus.com/inward/record.url?scp=85033449922&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85033449922&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.6b00392

DO - 10.1021/acsmedchemlett.6b00392

M3 - Article

C2 - 28105281

AN - SCOPUS:85033449922

VL - 8

SP - 90

EP - 95

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 1

ER -