Discovery and Optimization of a Novel Series of Pyrazolopyrimidines as Spermine Oxidase Inhibitors
Spermine oxidase (SMOX) is associated with pathological processes in cancer initiation and progression, driving interest in the search for SMOX inhibitors. Currently available inhibitors exhibit moderate activity and limited selectivity toward other polyamine-metabolizing enzymes such as polyamine oxidase (PAOX), underscoring the urgent need for potent and selective inhibitors of SMOX. This study focuses on the optimization of a series of pyrazolopyrimidines, leading to the discovery of JNJ-9350 as a potent inhibitor of human SMOX (hSMOX) with unprecedented selectivity over other polyamine enzymes such as hPAOX. Importantly, JNJ-9350 displays remarkable intracellular target engagement and inhibition in cellular assays, positioning JNJ-9350 as a suitable tool compound for cellular experiments to further validate the potential of SMOX inhibitors as anticancer therapeutics.
Authors
- Jackie Shang (ORCID: https://orcid.org/0000-0002-0661-528X)
- Antonietta Impagliazzo (ORCID: https://orcid.org/0000-0001-6202-4823)
- G. C. Gibbons
- José M. Cid (ORCID: https://orcid.org/0000-0002-4774-8361)
- Josep Llaveria (ORCID: https://orcid.org/0000-0003-2260-3657)
- María Lourdes Linares
- Lichao Fang (ORCID: https://orcid.org/0000-0002-8473-6095)
- Antonio Misale (ORCID: https://orcid.org/0000-0002-1866-0109)
- Daniel J. Krosky (ORCID: https://orcid.org/0000-0003-1567-6372)
- Christophe Buyck (ORCID: https://orcid.org/0000-0002-5711-1161)
- A. Dieguez-Vazquez (ORCID: https://orcid.org/0000-0003-0243-0357)
- Carolina Martínez Lamenca
- Elsie Diaz
- Meghan McCabe Pryor (ORCID: https://orcid.org/0009-0004-5068-7151)
- Vincent N. A. Klaren (ORCID: https://orcid.org/0009-0007-8935-6343)
- Suraj Adhikary (ORCID: https://orcid.org/0000-0003-1073-0966)
- Javier Suárez (ORCID: https://orcid.org/0009-0003-3173-9799)
- Santiago Cañellas (ORCID: https://orcid.org/0000-0002-8700-4615)
- Francisca Delgado
- Froylan Omar Fernandez Candelaria (ORCID: https://orcid.org/0000-0001-8074-1404)
- Ben Danna
Institutions
- Johnson & Johnson (United States) (US)
- Janssen (Belgium) (BE)
- Johnson & Johnson (United Kingdom) (GB)
- Janssen (Netherlands) (NL)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01449
- Primary Topic
- Polyamine Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00