Beckman Research Institute of City of Hope, Duarte, CA, USA.
FEBS Lett. 2021 Oct;595(20):2570-2592. doi: 10.1002/1873-3468.14186. Epub 2021 Sep 15.
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.
我们首次描述了 p38γ 丝裂原活化蛋白激酶（MAPK）中的一个脂质结合域（LBD），该域参与 T 细胞对新鉴定的抑制剂 CSH71 的反应。我们描述了 CSH71 如何结合 p38γ 的 LBD 和 ATP 结合口袋，对 CTCL Hut78 细胞具有选择性细胞毒性，但对正常健康的外周血单核细胞（PBMC）细胞没有毒性，并提出了其作用的可能分子机制。p38γ 是 CTCL 发展的关键因素，我们预计通过特异性靶向脂质结合域来调节其表达的能力将具有重要的临床意义。我们的发现描述了 T 淋巴瘤细胞中基因调控的新机制，并验证了计算筛选技术在鉴定治疗开发抑制剂方面的应用。
