8G63

Ralimetinib (LY2228820) in complex with wild type EGFR

8G63 の概要

• エントリーDOI: 10.2210/pdb8g63/pdb
• 分子名称: Epidermal growth factor receptor, ralimetinib (3 entities in total)
• 機能のキーワード: kinase inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37724.65

構造登録者

Chitnis, S.P.,Heppner, D.E. (登録日: 2023-02-14, 公開日: 2023-10-11, 最終更新日: 2024-04-24)

主引用文献

Bhattacharjee, D.,Bakar, J.,Chitnis, S.P.,Sausville, E.L.,Ashtekar, K.D.,Mendelson, B.E.,Long, K.,Smith, J.C.,Heppner, D.E.,Sheltzer, J.M.
Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor.
Cell Chem Biol, 30:1211-1222.e5, 2023

PubMed Abstract: The small-molecule drug ralimetinib was developed as an inhibitor of the p38α mitogen-activated protein kinase, and it has advanced to phase 2 clinical trials in oncology. Here, we demonstrate that ralimetinib resembles EGFR-targeting drugs in pharmacogenomic profiling experiments and that ralimetinib inhibits EGFR kinase activity in vitro and in cellulo. While ralimetinib sensitivity is unaffected by deletion of the genes encoding p38α and p38β, its effects are blocked by expression of the EGFR-T790M gatekeeper mutation. Finally, we solved the cocrystal structure of ralimetinib bound to EGFR, providing further evidence that this drug functions as an ATP-competitive EGFR inhibitor. We conclude that, though ralimetinib is >30-fold less potent against EGFR compared to p38α, its ability to inhibit EGFR drives its primary anticancer effects. Our results call into question the value of p38α as an anticancer target, and we describe a multi-modal approach that can be used to uncover a drug's mechanism-of-action.

PubMed: 37827156
DOI: 10.1016/j.chembiol.2023.09.013

実験手法

X-RAY DIFFRACTION (2.5 Å)