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 | |
| State | Published - Jan 1 2017 |
Fingerprint
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 journal › Article
}
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
PY - 2017/1/1
Y1 - 2017/1/1
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 -