# Synthesized Depside Molecules Suppress the Progression of Colorectal Cancer by Binding VDAC1/PHB/MMP9 Being at the Crossroads of Stemness, Motility, Apoptosis, and Metabolism

## TL;DR

New depside compounds target key proteins to suppress colorectal cancer growth by affecting stemness, motility, and metabolism.

## Contribution

Synthesis of depside compounds that directly target VDAC1/PHB/MMP9 to inhibit colorectal cancer progression.

## Key findings

- SB4 and SB5 showed strong cytotoxicity and suppressed cancer stem cell characteristics.
- The compounds inhibited cell motility and mitochondrial respiration while inducing apoptosis.
- SB4 demonstrated higher bioavailability and inhibited tumor growth in a mouse model.

## Abstract

Lichen secondary metabolites have shown potential in cancer therapy, but strategies to enhance cancer‐specific selectivity are needed. Here, we synthesized depside compounds structurally related to tumidulin (TU) and diffractaic acid (DA) and screened them in vitro, identifying SB4 and SB5 as potent hits. Affinity‐based proteomics revealed direct binding to voltage‐dependent anion channel 1 (VDAC1), prohibitin (PHB), and matrix metalloproteinase‐9 (MMP9), which regulate cancer stemness, motility, metabolism, and apoptosis. SB4 and SB5 exhibited strong cytotoxicity, suppressed cancer stem cell characteristics, inhibited cell motility, impaired mitochondrial respiration, induced reactive oxygen species, and promoted apoptosis. Notably, they reversed cetuximab‐induced cancer stemness in colorectal adenocarcinoma‐enriched stem cells. In vivo, SB4 and SB5 displayed higher tumor, liver, and intestinal bioavailability than TU and DA following intraperitoneal administration. Pharmacokinetic analyses indicated SB4 had a comparable absorption profile to SB5 with distinct systemic exposures differences. In a CT26/near‐infrared fluorescent protein tumor model, SB4 markedly inhibited tumor growth and modulated key markers of stemness, motility, metabolism, and apoptosis in tumor tissues. Collectively, these findings demonstrate that SB4 and SB5 are promising candidates for colorectal cancer therapy by targeting VDAC1/PHB/MMP9.

This study suggests that newly synthesized depside compounds suppress the progression of colorectal cancer by directly targeting VDAC1/PHB/MMP9. Especially, SB4 demonstrated significant bioavailability and successfully suppressed the tumor growth.