9LTA

Crystal Structure of Compound SKLB-D18 with MAPK7 (ERK5)

これはPDB形式変換不可エントリーです。

9LTA の概要

• エントリーDOI: 10.2210/pdb9lta/pdb
• 分子名称: Mitogen-activated protein kinase 7, 4-[5-chloranyl-2-[[3-[(dimethylamino)methyl]phenyl]amino]pyrimidin-4-yl]-~{N}-morpholin-4-yl-thiophene-2-carboxamide (3 entities in total)
• 機能のキーワード: erk5, inhibitor, cancer, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 80431.51

構造登録者

Xiao, H.,Sun, Q. (登録日: 2025-02-05, 公開日: 2025-04-02)

主引用文献

Xiao, H.,Wang, A.,Shuai, W.,Qian, Y.,Wu, C.,Wang, X.,Yang, P.,Sun, Q.,Wang, G.,Ouyang, L.,Sun, Q.
A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy.
Signal Transduct Target Ther, 10:70-70, 2025

PubMed Abstract: Despite significant advancements in kinase-targeted therapy, the emergence of acquired drug resistance to targets such as KRAS and MEK remains a challenge. Extracellular-regulated kinase 1/2 (ERK1/2), positioned at the terminus of this pathway, is highly conserved and less susceptible to mutations, thereby garnering attention as a crucial therapeutical target. However, attempts to use monotherapies that target ERK1/2 have achieved only limited clinical success, mainly due to the issues of limited efficacy and the emergence of drug resistance. Herein, we present a proof of concept that extracellular-regulated kinase 5 (ERK5) acts as a compensatory pathway after ERK1/2 inhibition in triple-negative breast cancer (TNBC). By utilizing the principle of polypharmacology, we computationally designed SKLB-D18, a first-in-class molecule that selectively targets ERK1/2 and ERK5, with nanomolar potency and high specificity for both targets. SKLB-D18 demonstrated excellent tolerability in mice and demonstrated superior in vivo anti-tumor efficacy, not only exceeding the existing clinical ERK1/2 inhibitor BVD-523, but also the combination regimen of BVD-523 and the ERK5 inhibitor XMD8-92. Mechanistically, we showed that SKLB-D18, as an autophagy agonist, played a role in mammalian target of rapamycin (mTOR)/70 ribosomal protein S6 kinase (p70S6K) and nuclear receptor coactivator 4 (NCOA4)-mediated ferroptosis, which may mitigate multidrug resistance.

PubMed: 39979271
DOI: 10.1038/s41392-025-02169-z

実験手法

X-RAY DIFFRACTION (2.33 Å)