Raloxifene, a SERM targets PD-L1: an in-silico study

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Cancer immunotherapies like monoclonal antibodies are effective but costly.
• There is a need for affordable small molecule inhibitors targeting immune checkpoints.
• Programmed death-ligand 1 (PD-L1) is a key immune checkpoint target.

Purpose of the Study:

• To investigate raloxifene, a selective estrogen receptor modulator (SERM), as a potential small molecule inhibitor of PD-L1.
• To establish raloxifene as a ligand for the immune checkpoint protein PD-L1.
• To explore raloxifene as a cost-effective alternative for cancer immunotherapy.

Main Methods:

• Utilized in silico approaches including similarity-search and drug-likeness analysis.
• Performed ligand-docking using Autodock to identify lead molecules against PD-L1.
• Conducted in vitro studies including cytotoxicity (SRB assay) and cellular migration (scratch assay) on HCT116 cells.

Main Results:

• In silico analysis showed raloxifene has high drug-likeness and strong binding affinity to PD-L1, comparable to positive controls.
• Raloxifene binds to the same site as FDA-approved antibodies like atezolizumab and durvalumab.
• In vitro studies demonstrated a time-dependent reduction in IC50 values and significant inhibition of HCT116 cell migration.

Conclusions:

• Raloxifene is identified as a potential in silico target of PD-L1.
• This research supports the development of small-molecule inhibitors for immune checkpoint blockade.
• Raloxifene presents a promising avenue for developing more accessible cancer immunotherapies.