# Drug repurposing reveals posaconazole as a CYP11A1 inhibitor enhancing anti-tumor immunity

## TL;DR

This study shows that posaconazole, a repurposed drug, inhibits steroid production and boosts anti-tumor immunity in a mouse model of lung metastasis.

## Contribution

The study identifies posaconazole as a novel CYP11A1 inhibitor through drug repurposing and demonstrates its anti-tumor effects in vivo.

## Key findings

- Posaconazole inhibits CYP11A1 by forming hydrogen bonds and hydrophobic interactions with key residues.
- Posaconazole reduces steroidogenesis and restricts lung metastasis in mice by enhancing anti-tumor immunity.

## Abstract

Steroid hormones regulate cell physiology and immune function, with dysregulated steroidogenesis promoting cancer progression by supporting tumor growth and suppressing anti-tumor immunity. Targeting CYP11A1, the first and rate-limiting enzyme in steroid biosynthesis, has shown promise in cancer therapy, but safe and effective inhibitors remain an unmet need. Undertaking in silico structure-based drug repurposing approach, we found posaconazole as an inhibitor of CYP11A1. The docking pose analysis showed that posaconazole can form multiple hydrogen bonds and hydrophobic interactions with the key residues at the binding site and the cofactor, stabilizing the protein-ligand complex. We validated its inhibition efficiency in cell-based assays. In a mouse model of lung metastasis, we demonstrated that posaconazole restricts metastasis by stimulating anti-tumor immunity. These findings highlight posaconazole’s potential as a research tool to study steroidogenesis and as a candidate for further preclinical and clinical evaluation in pathologies associated with local steroidogenesis, such as steroidogenic tumors.

•Drug repurposing identifies posaconazole as an inhibitor of CYP11A1•Posaconazole inhibits steroidogenesis•Posaconazole induces anti-tumor immunity and restricts lung metastasis in mice

Drug repurposing identifies posaconazole as an inhibitor of CYP11A1

Posaconazole inhibits steroidogenesis

Posaconazole induces anti-tumor immunity and restricts lung metastasis in mice

Pharmacology; Natural sciences; Biological sciences; Systems biology; Cancer systems biology