Structure of human spermine oxidase in complex with a highly selective allosteric inhibitor

  • Commun Biol. 2022 Aug 5;5(1):787. doi: 10.1038/s42003-022-03735-9.
Elsie Diaz   #  1 ,  Suraj Adhikary   #  1 ,  Armand W J W Tepper   #  2 ,  Daniel Riley  1 ,  Rodrigo Ortiz-Meoz  1 ,  Daniel Krosky  1 ,  Christophe Buyck  3 ,  Carolina Martinez Lamenca  3 ,  Josep Llaveria  4 ,  Lichao Fang  5 ,  Jay H Kalin  1 ,  Vincent N A Klaren  2 ,  Shorouk Fahmy  2 ,  Paul L Shaffer  1 ,  Robert Kirkpatrick  1 ,  Rodrigo J Carbajo  4 ,  Maren Thomsen  6 ,  Antonietta Impagliazzo  7  8
Affiliations
  • 1. Janssen Research & Development, Welsh & McKean Roads, Spring House, PA, 19477-0776, USA.
  • 2. Janssen Vaccine and Prevention, Archimedesweg 4-6, 2301, CA, Leiden, The Netherlands.
  • 3. Janssen Research & Development, Turnhoutseweg 30, B-2340, Beerse, Belgium.
  • 4. Janssen Research & Development, Janssen-Cilag, Discovery Chemistry S.A. Río Jarama, 75A, 45007, Toledo, Spain.
  • 5. Janssen Research & Development Center Medicinal Chemistry, Shanghai, 201210, China.
  • 6. Proteros biostructures GmbH Bunsenstr 7a, D-82152, Martinsried, Germany.
  • 7. Janssen Vaccine and Prevention, Archimedesweg 4-6, 2301, CA, Leiden, The Netherlands. [email protected].
  • 8. Genmab B.V. Uppsalalaan 15, 3584, CT, Utrecht, The Netherlands. [email protected].
  • # Contributed equally.
PMID: 35931745 DOI: 10.1038/s42003-022-03735-9
Abstract

Human spermine oxidase (hSMOX) plays a central role in polyamine catabolism. Due to its association with several pathological processes, including inflammation and Cancer, hSMOX has garnered interest as a possible therapeutic target. Therefore, determination of the structure of hSMOX is an important step to enable drug discovery and validate hSMOX as a drug target. Using insights from hydrogen/deuterium exchange mass spectrometry (HDX-MS), we engineered a hSMOX construct to obtain the first crystal structure of hSMOX bound to the known polyamine oxidase inhibitor MDL72527 at 2.4 Å resolution. While the overall fold of hSMOX is similar to its homolog, murine N1-acetylpolyamine oxidase (mPAOX), the two structures contain significant differences, notably in their substrate-binding domains and active site pockets. Subsequently, we employed a sensitive biochemical assay to conduct a high-throughput screen that identified a potent and selective hSMOX inhibitor, JNJ-1289. The co-crystal structure of hSMOX with JNJ-1289 was determined at 2.1 Å resolution, revealing that JNJ-1289 binds to an allosteric site, providing JNJ-1289 with a high degree of selectivity towards hSMOX. These results provide crucial insights into understanding the substrate specificity and enzymatic mechanism of hSMOX, and for the design of highly selective inhibitors.

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