# 4‐(5‐Chloro‐3‐(3,4,5‐trimethoxybenzoyl)‐1H‐indol‐1‐yl)benzenesulfonamide: A Novel Polypharmacology Agent to Target Carbonic Anhydrase IX and XII With Improved Selectivity, Wnt/β‐Catenin Signaling Pathway, and P‐Glycoprotein

## TL;DR

Researchers developed a new compound that targets specific enzymes and pathways in cancer cells, showing strong antitumor potential with reduced side effects.

## Contribution

Compound 15 is a novel polypharmacology agent with improved selectivity for hCA IX and XII, and inhibits Wnt/β-catenin and P-gp.

## Key findings

- Compound 15 selectively inhibits hCA IX and XII with high potency.
- It inhibits the Wnt/β-catenin pathway and restores drug sensitivity in resistant cancer cells.
- Compound 15 shows strong antitumor activity and acceptable metabolic stability.

## Abstract

We synthesized novel pyrrole (5–11) and indole (12–16) derivatives based on a polypharmacology approach aimed to obtain inhibitors of human carbonic anhydrase (hCA) with improved selectivity toward the IX and XII isoforms, Wnt/β‐catenin pathway, and P‐glycoprotein (P‐gp). Inspection of the binding sites of the hCA I, II, IX, and XII isoforms highlighted small but significant differences of cavity volumes that guided the introduction of small substituents at Position 4 of the 3‐phenyl ring of the pyrrole and at Position 5 of the indole. Compound 15 exhibited potent and selective inhibition of both hCA IX and XII isoforms compared to the parent compound. It inhibited the Wnt/β‐catenin pathway abrogating the association of β‐catenin with TCF‐4 and the multidrug‐resistant P‐gp‐expressing cancer cells. Compound 15 showed strong inhibition of viability of SW620, SW480, and HCT116 CRC and TNBC cell lines, restored the sensitivity to doxorubicin (DOX) in HT29/DX P‐gp‐overexpressing cells, and showed medium metabolic stability in both human and mouse microsomes and acceptable predicted oral bioavailability. Compound 15 is a robust lead compound for the development of new antitumor agents based on the polypharmacology approach.

Polypharmacology is expected to produce higher therapeutic efficacy and lower cytotoxic and side effects. Compound 15 exhibited strong inhibition of the human carbonic anhydrase isoforms IX and XII and selectivity toward the adverse isoforms I and II. It inhibited strongly the Wnt/β‐catenin pathway and the multidrug‐resistant P‐gp‐expressing cancer cells. Compound 15 showed potential as a new polypharmacology antitumor agent.© 2026 WILEY‐VCH GmbH