# The anabolic steroid stanozolol is a potent inhibitor of human MutT homolog 1

## TL;DR

This study shows that the anabolic steroid stanozolol strongly inhibits the enzyme hMTH1, which is a potential target for anticancer drugs.

## Contribution

Stanozolol is identified as a potent and unexpected inhibitor of hMTH1 with a unique binding scaffold.

## Key findings

- Stanozolol inhibits hMTH1 at nanomolar concentrations.
- The crystal structure of hMTH1 bound to stanozolol reveals a unique binding scaffold.
- hMTH1's structure is unrelated to proteins that bind dihydrotestosterone.

## Abstract

Human MutT homolog 1 (hMTH1) removes damaged nucleotides from the nucleotide pool, preventing their incorporation into DNA. Due to its potential as an anticancer drug target, hMTH1 has been the focus of several inhibitor development studies. Unexpectedly, we show that the anabolic steroid stanozolol (Stz) is a potent nanomolar inhibitor of hMTH1. We present the structure of hMTH1 in complex with Stz, which indicates a unique core scaffold that could be exploited for future inhibitor development. Comparison with human protein structures bound with dihydrotestosterone (DHT) shows hMTH1 is entirely unrelated in terms of its structure. As these DHT binding proteins are all involved in steroid regulation, this makes the identification of Stz as a potent hMTH1 inhibitor all the more unusual.

MutT homolog 1 (MTH1) is a member of the NUDIX superfamily of enzymes and is an anticancer drug target. We show that stanozolol (Stz), an anabolic steroid, is an unexpected nanomolar inhibitor of MTH1. The X‐ray crystal structure of the human MTH1–Stz complex reveals a unique binding scaffold that could be utilized for future inhibitor development.