Discovery of novel CA-4 analogs as dual inhibitors of tubulin polymerization and PD-1/PD-L1 interaction for cancer treatment.

Abstract

A series of novel CA-4 analogs as dual inhibitors of tubulin polymerization and PD-1/PD-L1 were designed, synthesized and bio-evaluated. Among them, compound TP5 exhibited strongest inhibitory effects against five cancer cell lines with an IC50 value of 800nM in HepG2 cells. In addition, mechanism studies revealed that TP5 could effectively inhibit tubulin polymerization, suppress HepG2 cells migration and colony formation, and cause cell arrest at G2/M phase and induce apoptosis. Furthermore, TP5 exhibited moderate anti-PD-1/PD-L1 activity with IC50 values of 48.76μM in a homogenous time-resolved fluorescence (HTRF) assay. Invivo efficacy studies indicated that TP5 could significantly suppress tumor growth in an immune checkpoint humanized mouse model with a Tumor Growth Suppression (TGI) of 57.9% at 100mg/kg without causing significant toxicity. Moreover, TP5 did not cause invivo cardiotoxicity in BALB/c mice. These results suggest that the novel CA-4 analogs may serve as a starting point for developing more potent dual inhibitors of tubulin polymerization and PD-1/PD-L1.