PI-044 - DISRUPTING THE PD-L1 AND PDS5B INTERACTION BY COMPOUNDS: A PROMISING THERAPEUTIC STRATEGY FOR TRIPLE-NEGATIVE BREAST CANCER.

M. Wang¹, N. Islam², M. Coban², C. Webber², H. Gao³, X. Wang¹, D. Liu¹, R. Weinshilboum¹, T. Caulfield², L. Wang¹; ¹Mayo Clinic, Rochester, MN, USA, ²Mayo Clinic, Jacksonville, FL, USA, ³Mayo Clinic, Rochester, USA.

Background: In addition to its role as a transmembrane immune checkpoint that enables tumor cells to evade the immune system, PD-L1 was found in the nucleus of triple-negative breast cancer (TNBC) cells which was associated with poor prognosis. Specifically, nuclear PD-L1 interacts with the cohesin complex, competing with WAPL for binding to PDS5B, a cohesin component, thereby stabilizing the cohesin ring and maintaining cancer cell genomic stability. Blockade of PD-L1-PDS5B binding may be a novel therapeutic strategy for TNBC treatment.

Methods: This study was designed to identify compounds that disrupt PD-L1-PDS5B binding. Compounds were screened in silico using the SWEETLEAD and SAVI databases based on a pharmacophore model from the YSR-like motif and the PDS5B binding pocket. Binding affinity for these compounds was accessed by molecular docking. Top-ranked compounds were selected for cytotoxicity testing in a TNBC cell line, MDA-MB-231. IC50 values for each compound were determined for potency. Co-immunoprecipitation (Co-IP) assays were performed to confirm each compound’s ability to disrupt the PD-L1-PDS5B interaction.

Results: In silico screening identified 20 compounds that potentially disrupted the PD-L1-PDS5B interaction. Six of those 20 demonstrated potent cytotoxic effects in TNBC cells at a single dose (10 µM). Subsequent IC50 analysis revealed three compounds—Compound A, Compound B, and Compound C-with IC50 values below 10 µM, making them promising candidates for further evaluation. Co-IP of PD-L1 confirmed that all three compounds disrupted the PD-L1-PDS5B interaction, with Compound C showing the strongest effect, reducing PD-L1-PDS5B binding by over 50%. Additionally, Compound C induced apoptosis of TNBC cells, highlighting its possible therapeutic potential. Structural analysis suggested that Compound C may interact with the PD-L1 binding site on PDS5B, thus disrupting cohesin complex function.

Conclusion: We identified three compounds capable of disrupting the PD-L1-PDS5B interaction and inhibiting TNBC cell growth, indicating their potential as possible therapeutic agents for TNBC. Ongoing research will focus on broadening compound screening and optimizing those compounds to improve efficacy, lower IC50 values, and enhance drug-like properties, thus advancing their potential as targeted therapies for TNBC.