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

Objectives: Immunotherapeutic interventions in cancer have been considerably successful and widely accepted for cancer treatment, but are costly and cannot be afforded by all patients.

Because of the high cost, the pharmaceutical research groups across the world are sufficiently motivated to discover or design small molecule inhibitors to treat cancer through inhibition of the immune checkpoint proteins previously targeted with monoclonal antibodies.

The presented study was designed with an aim to establish raloxifene, a selective estrogen receptor modulator (SERM) as a potential ligand of the immune checkpoint protein Programmed death ligand-1 (PD-L1).

Methods: In the presented study, the in-silico approach was used for identifying a lead molecule against PD-L1.

The hits were screened using the similarity-search method, and drug-likeliness analysis, and the leads were identified through ligand-docking using Autodock.

In-vitro cytotoxicity analysis was carried out using the standard sulphorhodamine B (SRB) assay and the wound healing analysis to show the inhibition of cellular migration was performed using the standard scratch assay.

Results: The in-silico study revealed that raloxifene showed a high drug likelihood and higher binding affinity with PD-L1 as compared to the positive control (BMS-1166; BMS is Bristol Myers Squibb).

The binding of raloxifene was shown to occur in the same region as the FDA-approved monoclonal antibodies atezolizumab and durvalumab, indicating the potential of raloxifene for PD1/PD-L1 blockade.

In the in-vitro studies, raloxifene showed a time-dependent reduction in IC(50) values for the cell line HCT116 (colon cancer).

The scratch assay also revealed that raloxifene significantly reduced the migratory potential of HCT-116 cells in-vitro.

Conclusions: PD-L1 is a potential target of the SERM raloxifene in-silico.

Overall, this study is one step further towards immune checkpoint blockade using small-molecule inhibitors.