Discovery of a New Scaffold RSK2 Inhibitor With Virtual and Phenotypical Screening

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Cancer Biology

Background:

• Ribosomal S6 kinase 2 (RSK2) is a key target in breast and ovarian cancer therapy.
• Existing RSK2 inhibitors often lack selectivity and optimal pharmacokinetic profiles due to similar chemical structures.
• There is a critical need for novel RSK2 inhibitors with enhanced potency, selectivity, and drug-like properties.

Purpose of the Study:

• To identify novel, potent, and selective inhibitors of RSK2.
• To discover a promising lead compound for further drug development against RSK2-driven cancers.
• To develop a chemical tool for investigating RSK2's biological functions.

Main Methods:

• A virtual screening workflow integrating pharmacophore modeling, molecular docking, and molecular dynamics simulations was employed.
• The Chemdiv database, containing 1.6 million compounds, was screened.
• Phenotypic screening, surface plasmon resonance (SPR) assays, and cell-based assays were utilized for validation.

Main Results:

• The virtual screening identified 39 potential RSK2 inhibitors from the Chemdiv database.
• Compound M39 emerged as a promising cell-active RSK2 inhibitor.
• M39 demonstrated binding to RSK2 with a dissociation constant (Kd) of 156 nM, inhibited RSK2 catalytic activity by suppressing YB1 phosphorylation, and exhibited superior anti-tumor efficacy compared to LJH685 in breast and ovarian cancer cells.

Conclusions:

• Compound M39, possessing a unique chemical scaffold, represents a promising lead for RSK2 inhibitor optimization.
• M39 serves as a valuable chemical probe for exploring the biological roles of RSK2.
• The identified compound holds potential for the development of new therapeutic strategies against breast and ovarian cancers.