# Chalcone-containing dual-targeting PD-L1/tubulin small molecules: a novel approach for cancer immunotherapy

## TL;DR

This study identifies a new compound that targets both PD-L1 and tubulin, offering a dual-action approach for cancer immunotherapy.

## Contribution

The paper introduces a novel small molecule with dual-targeting capabilities for PD-L1 and tubulin in cancer treatment.

## Key findings

- Compound PP-1 inhibits PD-1/PD-L1 interaction and tubulin polymerization with IC50 values of 81.1 µM and 70.1 µM, respectively.
- PP-1 showed significant antitumor efficacy in a melanoma model with 42% tumor growth inhibition and no systemic toxicity.
- Molecular docking confirmed PP-1's ability to bind both PD-L1 and tubulin, supporting its dual-targeting mechanism.

## Abstract

This study aims to identify novel small-molecule inhibitors capable of dual targeting of PD-L1 and tubulin, intending to enhance cancer immunotherapy.

A combination of computer-aided virtual screening, molecular docking, homogeneous time-resolved fluorescence (HTRF) assays, tubulin polymerization inhibition assays, and in vivo antitumor assays was utilized to identify compounds with dual-targeting potential.

Compound PP-1 exhibited moderate inhibitory activity against the PD-1/PD-L1 interaction (IC50 = 81.1 µM) and showed dose-dependent inhibition of tubulin polymerization (IC50 = 70.1 µM). Molecular docking analysis further confirmed that PP-1 can effectively bind to both PD-L1 and tubulin at the molecular level, supporting its bifunctional targeting capability. Importantly, compound PP-1 (50 mg/kg, P.O.) demonstrated significant antitumor efficacy in a melanoma model, achieving a tumor growth inhibition rate of 42% without apparent systemic toxicity.

PP-1 demonstrates dual-target inhibitory activity against both the PD-1/PD-L1 immune checkpoint and tubulin polymerization, underscoring its potential as a promising lead compound for the development of next-generation dual-functional anticancer agents.