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p38α Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma

Ling Yang1, Xiaoting Sun2, Ying Ye3

  • 1Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Frontiers in Oncology
|December 13, 2019
PubMed

Insights

p38 mitogen-activated protein kinase alpha (p38α) is activated in pancreatic cancer. Understanding its dynamics and flexible regions offers new targets for developing more selective anti-cancer therapies.

Area of Science:

  • Molecular biology
  • Biochemistry
  • Cancer research

Background:

  • p38 mitogen-activated protein kinases (MAPKs) are key signaling molecules in cancer.
  • Understanding p38 MAPK function is crucial for targeted cancer therapy.
  • p38α, a prominent p38 MAPK member, has poorly understood conformational dynamics.

Purpose of the Study:

  • Investigate the role of p38α in pancreatic adenocarcinoma.
  • Elucidate the conformational dynamics of p38α.
  • Identify novel drug targets for pancreatic cancer therapy.

Main Methods:

  • Long-timescale molecular dynamics simulations (39 μs) on the Anton supercomputer.
  • In vitro studies using human and mouse pancreatic cancer cell lines.
  • Computational solvent mapping for drug design.

Main Results:

  • p38α is significantly activated in pancreatic adenocarcinoma.
  • Apo p38α exhibits high structural flexibility in six distinct regions.
  • A potential catalysis mechanism involving "butterfly" motion was identified.
  • Current p38α inhibitors show low selectivity in pancreatic cancer cells.
  • 17 novel druggable pockets in p38α were identified.

Conclusions:

  • The study reveals critical conformational dynamics of p38α.
  • Identified flexible regions and novel pockets offer potential for p38α-targeted drug development.
  • Findings may lead to improved therapies for pancreatic cancer patients.
Keywords:
conformational dynamicsmolecular dynamicsp38αpancreatic cancertumor targeted therapy

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