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.
Bibliographical noteFunding 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.
- Anticancer agents
- Autophagy modulator
- Pancreatic cancer