TY - JOUR
T1 - Targeting STAT3 by a small molecule suppresses pancreatic cancer progression
AU - Chen, Huang
AU - Bian, Aiwu
AU - Yang, Lian fang
AU - Yin, Xuan
AU - Wang, Jie
AU - Ti, Chaowen
AU - Miao, Ying
AU - Peng, Shihong
AU - Xu, Shifen
AU - Liu, Mingyao
AU - Qiu, Wen Wei
AU - Yi, Zhengfang
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.
PY - 2021/2/25
Y1 - 2021/2/25
N2 - Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer.
AB - Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer.
UR - https://www.scopus.com/pages/publications/85098945414
U2 - 10.1038/s41388-020-01626-z
DO - 10.1038/s41388-020-01626-z
M3 - 文章
C2 - 33420372
AN - SCOPUS:85098945414
SN - 0950-9232
VL - 40
SP - 1440
EP - 1457
JO - Oncogene
JF - Oncogene
IS - 8
ER -
