P38? Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma.

ABSTRACT: 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, p38?, are crucial for its function but poorly understood. Here we found that, unlike in other cancer types, p38? 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 ?s) unbiased molecular dynamics simulations of p38? show that apo p38? has high structural flexibility in six regions, and reveal potential catalysis mechanism involving a "butterfly" motion. Moreover, in vitro studies show the low-selectivity of the current p38? 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 p38?, which may potentiate p38?-targeting drug development and benefit pancreatic cancer patients.

SUBMITTER: Yang L 

PROVIDER: S-EPMC6890821 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature