Impact Factor 4.137 | CiteScore 4.28
More on impact ›

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01294

p38α mitogen-activated protein kinase is a druggable target in pancreatic adenocarcinoma

 Ling Yang1,  Xiaoting Sun2, Ying Ye3, Yongtian Lu4, Ji Zuo1, Wen Liu1, Adrian Elcock5 and  Shun Zhu1*
  • 1Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, China
  • 2Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, China
  • 3Shanghai Dental Tissue Repair and Regeneration Engineering Technology Research Center, China
  • 4Shenzhen Second People's Hospital, China
  • 5Department of Biochemistry, Carver College of Medicine, University of Iowa, United States

p38 mitogen-activated protein kinases are signaling molecules with major involvement in cancer. A detailed mechanistic understanding of how p38 MAPK family members function is urgently warranted for cancer targeted therapy. The conformational dynamics of the most common member of p38 MAPK family, p38α, are crucial for its function but poorly understood. Here we found that, unlike in other cancer types, p38α is significantly activated in pancreatic adenocarcinoma samples, suggesting its potential for anti-pancreatic cancer therapy. Using a state of the art supercomputer, Anton, long-timescale (39 us) unbiased molecular dynamics simulations of p38α show that apo p38α has high structural flexibility in 6 regions, and reveal potential catalysis mechanism involving a “butterfly” motion. Moreover, in vitro studies show the low-selectivity of the current p38α inhibitors in both human and mouse pancreatic cancer cell lines, while computational solvent mapping identified 17 novel pockets for drug design. Taken together, our study reveals the conformational dynamics and potentially druggable pockets of p38α, which may potentiate p38α-targeting drug development and benefit pancreatic cancer patients.

Keywords: P38α, molecular dynamics, tumor targeted therapy, conformational dynamics, Pancreatic Cancer

Received: 31 Oct 2019; Accepted: 07 Nov 2019.

Copyright: © 2019 Yang, Sun, Ye, Lu, Zuo, Liu, Elcock and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Shun Zhu, Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China, shun_zhu@fudan.edu.cn