A Special View of What Was Almost Forgotten: p38δ MAPK

SIMPLE SUMMARY: p38δ MAPK, as well as the other p38 isoforms, was proposed as a drug target for cancer therapy, owing to its critical roles in cellular signaling. However, herein, we show that p38δ inhibition may be therapeutically beneficial for treatment of specific cancer types, such as skin carcinoma, hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), cholangiocarcinoma (CC), and breast cancer. This review aims to discuss the roles of p38δ in cancer and summarize the findings of molecules with potential to inhibit p38δ in order to guide the search for new target cancer therapies based on p38δ inhibitors. ABSTRACT: The p38δ mitogen-activated protein kinase is an important signal transduction enzyme. p38δ has recently emerged as a drug target due to its tissue-specific expression patterns and its critical roles in regulation of cellular processes related to cancer and inflammatory diseases, such as cell proliferation, cell migration, apoptosis, and inflammatory responses. However, potent and specific p38δ inhibitors have not been defined so far. Moreover, in cancer disease, p38δ appears to act as a tumor suppressor or tumor promoter according to cancer and cell type studied. In this review, we outline the current understanding of p38δ roles in each cancer type, to define whether it is possible to delineate new cancer therapies based on small-molecule p38δ inhibitors. We also highlight recent advances made in the design of molecules with potential to inhibit p38 isoforms and discuss structural approaches to guide the search for p38δ inhibitors.