Bazedoxifene analogs as potential WDHD1 degraders and antitumor agents: Synthesis, evaluation and molecular dynamics...

Area of Science:

• Molecular Biology
• Biochemistry
• Oncology

Background:

• DNA repair mechanisms, particularly homologous recombination, are vital for tumor resistance to cancer therapies.
• Overexpression of WD repeat and HMG-box DNA binding protein 1 (WDHD1) correlates with poor patient prognosis in various cancers.
• WDHD1 acts as a key adaptor in DNA repair pathways.

Purpose of the Study:

• To investigate the binding mechanism of bazedoxifene (BZA) with WDHD1.
• To synthesize and evaluate novel BZA analogs for enhanced WDHD1 inhibition.
• To provide insights for developing new WDHD1-targeting cancer drugs.

Main Methods:

• Molecular docking to establish the initial binding model of BZA with WDHD1.
• Chemical synthesis of eight BZA analogs.
• Molecular dynamics simulations to analyze binding interactions and activity.
• In vitro assays to evaluate the inhibitory effects of BZA and its analogs on WDHD1.

Main Results:

• Bazedoxifene demonstrated a 60% inhibitory rate against WDHD1 in MCF7 cells at 10 μM.
• The study established the binding model of BZA with WDHD1.
• Eight BZA analogs were synthesized and evaluated, with some showing promising activity.

Conclusions:

• The established binding mode of BZA provides a structural basis for its inhibitory activity against WDHD1.
• This research facilitates the rational design of novel WDHD1 inhibitors and degraders for cancer treatment.
• Targeting WDHD1 offers a potential strategy to overcome tumor resistance to radiotherapy and chemotherapy.