(S,S)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-oxo-1-((1-(pyridin-4-yl)ethyl)amino)propan-2-yl)-1H-indole-2-carboxamide, a New Dishevelled 1 and P-Glycoprotein Dual Inhibitor as a Anticancer Agent.

内容摘要

Dishevelled (DVL) proteins are key mediators of the Wnt/β-catenin signaling pathway, involved in signal transduction from membrane receptors to intracellular effectors. DVL up-regulation has often been correlated with tumor progression and metastasis. DVL1 was found overexpressed in multidrug-resistant colorectal cancer (CRC) cells. Here, we describe the synthesis of new indole-2-carboxamides 2-18 as DVL1 inhibitors. Compound (S,S)-15 showed potent DVL1 inhibition with IC50 of 0.97 ± 0.21 μM and specific binding to the DVL1 PDZ domain. (S,S)-15 strongly reduced β-catenin expression in HCT116 CRC cells and significantly decreased tumor volume and weight in a xenograft model. Additionally, (S,S)-15 inhibited P-glycoprotein (P-gp), restoring sensitivity to doxorubicin (DOX) in HT29/DX CRC chemoresistant cells. (S,S)-15 demonstrated high metabolic stability in human liver microsomes, and an acceptable pharmacokinetic profile following IV administration in mice. Our findings indicate that compound (S,S)-15 represents a promising dual-targeting antitumor candidate for CRC treatment.