2. Academic Validation
  3. New Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma

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

  • J Med Chem. 2026 Feb 12;69(3):2310-2329. doi: 10.1021/acs.jmedchem.5c02154.
Amardeep Awasthi 1,  Anika Patel 2,  Huiying Li 3,  Koon Mook Kang 1,  Christine D Hardy 3,  Anas Ansari 1,  Raghad Nowar 1,  Md Emtiaz Hasan 2,  Sun Yang 2,  Thomas L Poulos 3,  Richard B Silverman 1 4 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Chemistry of Life Processes Institute, Center for Developmental Therapeutics, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
  • 2 Department of Pharmacy Practice, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, 9401 Jeronimo Road, Irvine, California 92618, United States.
  • 3 Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, California 92697-3900, United States.
  • 4 Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, United States.
  • 5 Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
PMID: 41615895 DOI: 10.1021/acs.jmedchem.5c02154
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.

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