New Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma
Amardeep Awasthi, Anika Patel, Huiying Li, Koon Mook Kang, Christine D. Hardy, Anas Ansari, Raghad Nowar, Md. Emtiaz Hasan, Sun Yang, Thomas L. Poulos, Richard B. Silverman
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.
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,…
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Taxonomy
TopicsNitric Oxide and Endothelin Effects · Electron Spin Resonance Studies · Metal-Catalyzed Oxygenation Mechanisms