Discovery and Optimization of PLK1 Inhibitors
Lead optimization by free energy perturbation (FEP)
Background
• PLK1 is overexpressed in a variety of human tumors, with elevated levels often linked to poor prognosis.
• Few PLK1 inhibitors have reached the clinical phase, but their efficacy, suboptimal exposure, and potential hematological toxicity highlight the need for improvement.
• Uni-FEP delives reliable free energy predictions within chemical accuracy (± 1 kcal/mol), and has been validated across drug discovery programs targeting kinases, GPCRs, PPIs, and more.
Project Workflow
Results
• By leveraging existing data for modeling, Uni-FEP accurately predicted the activity of chemist-designed molecules, showing strong alignment with experimental results.
• During the optimization of compound DP101, Uni-FEP effectively scored and ranked modifications across multiple sites, guiding structure-activity relationship (SAR) decisions.
Summary
• Molecule generation enabled the discovery of new lead compounds, while FEP-assisted structural optimization facilitated the development of a series of novel PLK1 inhibitors.
• DP226, featuring an optimized pharmacokinetic profile and improved safety, demonstrated superior anti-tumor activity, showing efficacy both as a monotherapy and in combination with bevacizumab.
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