Targeting the non-ATP-binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T-cell lymphoma (CTCL)

FEBS Lett. 2021 Oct;595(20):2570-2592. doi: 10.1002/1873-3468.14186. Epub 2021 Sep 15.

Abstract

We describe here for the first time a lipid-binding-domain (LBD) in p38γ mitogen-activated protein kinase (MAPK) involved in the response of T cells to a newly identified inhibitor, CSH71. We describe how CSH71, which binds to both the LBD and the ATP-binding pocket of p38γ, is selectively cytotoxic to CTCL Hut78 cells but spares normal healthy peripheral blood mononuclear (PBMC) cells, and propose possible molecular mechanisms for its action. p38γ is a key player in CTCL development, and we expect that the ability to regulate its expression by specifically targeting the lipid-binding domain will have important clinical relevance. Our findings characterize novel mechanisms of gene regulation in T lymphoma cells and validate the use of computational screening techniques to identify inhibitors for therapeutic development.

Keywords: ATP-binding pocket; NMR spectroscopy; TCR signaling pathway; TNF alpha; computational virtual screening of chemicals; cutaneous T-cell lymphoma; cytotoxicity; lipid-binding domain; the MAP kinase p38γ.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Antineoplastic Agents / therapeutic use
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphoma, T-Cell, Cutaneous / drug therapy
  • Lymphoma, T-Cell, Cutaneous / genetics
  • Lymphoma, T-Cell, Cutaneous / metabolism*
  • Mitogen-Activated Protein Kinase 12 / metabolism*
  • Signal Transduction
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*

Substances

  • Antineoplastic Agents
  • Adenosine Triphosphate
  • Mitogen-Activated Protein Kinase 12