Document Type
Article
Publication Date
1-30-2026
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 (Ki = 1.7 nM) and rat nNOS (Ki = 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.
Recommended Citation
Awasthi, A.; Patel, A.; Li, H.; Kang, K. M.; Hardy, C. D.; Ansari, A.; Nowar, R.; Hasan, M. E.; Yang, S.; Poulos, T. L.; Silverman, R. B. New Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma. J. Med. Chem. 2026, 69(3), 2310–2329. https://doi.org/10.1021/acs.jmedchem.5c02154
NOS enzyme inhibition assay and permeability assay; crystallographic data collection and refinement statistics for rat nNOS, human nNOS, and human eNOS; computational details for MD simulation; synthetic details and characterization for the key intermediates and the final compounds; and copies of NMR spectra and HPLC traces for the final compounds (1–21) (PDF)
jm5c02154_si_002.csv (4 kB)
Molecular formula strings (CSV)
Copyright
The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
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Cancer Biology Commons, Medicinal and Pharmaceutical Chemistry Commons, Oncology Commons
Comments
This article was originally published in Journal of Medicinal Chemistry, volume 69, issue 3, in 2026. https://doi.org/10.1021/acs.jmedchem.5c02154