TY - JOUR
T1 - Induction of Genes Implicated in Stress Response and Autophagy by a Novel Quinolin-8-yl-nicotinamide QN523 in Pancreatic Cancer
AU - Kuang, Yuting
AU - Ye, Na
AU - Kyani, Armita
AU - Ljungman, Mats
AU - Paulsen, Michelle
AU - Chen, Haijun
AU - Zhou, Mingxiang
AU - Wild, Christopher
AU - Chen, Haiying
AU - Zhou, Jia
AU - Neamati, Nouri
N1 - Funding Information:
This work was supported by the NIH grant R01 CA188252 and a grant from the University of Michigan Forbes Institute for Cancer Discovery. J.Z. is partially supported by the John D. Stobo, M.D. Distinguished Chair Endowment Fund at UTMB. We gratefully acknowledge the University of Michigan DNA Sequencing Core and Bru-seq Core facilities for their excellent technical assistance.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/4/28
Y1 - 2022/4/28
N2 - Using a cytotoxicity-based phenotypic screen of a highly diverse library of 20,000 small-molecule compounds, we identified a quinolin-8-yl-nicotinamide, QN519, as a promising lead. QN519 represents a novel scaffold with drug-like properties, showing potent in vitro cytotoxicity in a panel of 12 cancer cell lines. Subsequently, lead optimization campaign generated compounds with IC50values < 1 μM. An optimized compound, QN523, shows significant in vivo efficacy in a pancreatic cancer xenograft model. QN523 treatment significantly increased the expression of HSPA5, DDIT3, TRIB3, and ATF3 genes, suggesting activation of the stress response pathway. We also observed a significant increase in the expression of WIPI1, HERPUD1, GABARAPL1, and MAP1LC3B, implicating autophagy as a major mechanism of action. Due to the lack of effective treatments for pancreatic cancer, discovery of novel agents such as the QN series of compounds with unique mechanism of action has the potential to fulfill a clear unmet medical need.
AB - Using a cytotoxicity-based phenotypic screen of a highly diverse library of 20,000 small-molecule compounds, we identified a quinolin-8-yl-nicotinamide, QN519, as a promising lead. QN519 represents a novel scaffold with drug-like properties, showing potent in vitro cytotoxicity in a panel of 12 cancer cell lines. Subsequently, lead optimization campaign generated compounds with IC50values < 1 μM. An optimized compound, QN523, shows significant in vivo efficacy in a pancreatic cancer xenograft model. QN523 treatment significantly increased the expression of HSPA5, DDIT3, TRIB3, and ATF3 genes, suggesting activation of the stress response pathway. We also observed a significant increase in the expression of WIPI1, HERPUD1, GABARAPL1, and MAP1LC3B, implicating autophagy as a major mechanism of action. Due to the lack of effective treatments for pancreatic cancer, discovery of novel agents such as the QN series of compounds with unique mechanism of action has the potential to fulfill a clear unmet medical need.
UR - http://www.scopus.com/inward/record.url?scp=85129035908&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129035908&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c02207
DO - 10.1021/acs.jmedchem.1c02207
M3 - Article
C2 - 35439009
AN - SCOPUS:85129035908
SN - 0022-2623
VL - 65
SP - 6133
EP - 6156
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -