# New Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma

## TL;DR

This paper presents new inhibitors of neuronal nitric oxide synthase (nNOS) that could help treat melanoma by selectively targeting nNOS with high efficiency.

## Contribution

The study introduces a novel structure-based design of highly selective nNOS inhibitors with improved activity and selectivity for melanoma treatment.

## Key findings

- Compound 9 showed strong inhibition of human and rat nNOS with high selectivity over eNOS and iNOS.
- X-ray crystallography and modeling revealed a new structure-activity relationship for nNOS inhibition.
- The findings provide a foundation for designing more effective nNOS inhibitors for melanoma.

## Abstract

In 2024, an estimated
100,640 new cases of invasive melanoma
were
diagnosed in the U.S., with 9290 deaths. Our previous studies revealed
that neuronal nitric oxide synthase (nNOS) derived nitric oxide plays
a critical role in melanoma progression, making nNOS inhibition a
promising strategy. High structural similarity among NOS isoforms
requires careful design of nNOS inhibitors to avoid off-target effects.
Our previous lead, HH044, demonstrated potent antimelanoma activity
but exhibited only moderate nNOS selectivity. Here, we utilized a
structure-based approach to design nNOS inhibitors that promote interactions
with human nNOS-specific residue His342. Compound 9 exhibited
inhibition of both human (K
i = 1.7 nM)
and rat nNOS (K
i = 2.3 nM), with 5654-fold
selectivity over human eNOS and 250-fold selectivity over iNOS. X-ray
crystallography and molecular modeling revealed a novel SAR, forming
the basis for nNOS inhibition and providing a foundation for further
innovative design of nNOS inhibitors for melanoma treatment.