The Discovery of Small ERK5 Inhibitors via Structure-Based Virtual Screening, Biological Evaluation and MD...

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Computational Drug Discovery

Background:

• Extracellular signal-regulated kinase 5 (ERK5) is a MAP kinase implicated in cancer progression.
• ERK5 regulates key cellular processes including proliferation, survival, and migration.
• Targeting ERK5 is a potential therapeutic strategy for various cancers.

Purpose of the Study:

• To identify novel inhibitors of ERK5 using structure-based virtual screening.
• To evaluate the antiproliferative and anti-migration activities of identified compounds.
• To assess the binding stability and affinity of lead compounds to ERK5.

Main Methods:

• Structure-based virtual screening of 1.6 million compounds using Schrodinger Maestro.
• Antiproliferative activity assessed via MTT assay in A549 and H292 lung cancer cell lines.
• Molecular dynamics simulations and MM-GB/SA scoring to evaluate binding stability and affinity.

Main Results:

• 40 candidate compounds were identified with superior docking scores.
• Compounds STK038175, STK300222, and GR04 exhibited significant antiproliferative activity (IC50: 10-25 µM).
• STK300222 reduced ERK5 phosphorylation and cell migration; MD simulations confirmed stable binding and strong interactions for STK300222 and GR04.

Conclusions:

• STK300222 and GR04 are promising ERK5 inhibitors with significant antiproliferative and anti-migration effects.
• These compounds demonstrate stable binding to ERK5, comparable to the co-crystallized ligand.
• Further optimization and in vivo validation of STK300222 and GR04 are warranted for cancer therapy development.