# NK-A 17E-233I: a novel competitive inhibitor of human dihydroorotate dehydrogenase (DHODH) for cancer therapy

## TL;DR

This paper introduces a new drug candidate that inhibits a key enzyme in cancer cell growth, showing better effectiveness and fewer side effects than existing treatments.

## Contribution

A novel competitive inhibitor of DHODH, NK-A 17E-233I, was developed with a distinct binding mode and improved therapeutic profile.

## Key findings

- NK-A 17E-233I selectively kills cancer cells and patient-derived organoids while preserving mitochondrial function.
- The compound induces DNA damage and S-phase arrest in cancer cells.
- It binds to DHODH differently from existing inhibitors, avoiding ETC impairment.

## Abstract

Human dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in pyrimidine de novo synthesis and represents a promising target for cancer therapy. However, current inhibitors of DHODH have limited clinical effectiveness and adverse effects. Herein, we report NK-A 17E-233I, a novel small-molecule inhibitor of the human DHODH enzyme, identified through a prospective virtual screening methodology. Molecular docking and biochemical assays show NK-A 17E-233I functions as a pure or partial competitive inhibitor with respect to the natural substrate, dihydroorotate (DHO). It adopts a distinct binding mode from classical inhibitors that target the flavin mononucleotide (FMN) binding cavity of the hydrophobic tunnel. NK-A 17E-233I exhibits selective cytotoxicity in both human cancer cell lines and patient-derived intestinal organoids, inducing DNA damage, S-phase arrest, and cell death. Unlike Brequinar, NK-A 17E-233I preserves mitochondrial respiration via complexes I and II and maintains ATP-linked basal respiration, avoiding the impairment of the electron transport chain (ETC). Our findings imply the aptitude of NK-A 17E-233I as a novel competitive inhibitor of human DHODH, representing a significant advancement in this field since the 1990s.

The online version contains supplementary material available at 10.1186/s13046-025-03538-w.