New Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of 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 5

SUBMITTER: Awasthi A 

PROVIDER: S-EPMC12895717 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature