2. Academic Validation
  3. Discovery of a spirocyclic 3-bromo-4,5-dihydroisoxazole covalent inhibitor of hGAPDH with antiproliferative activity against pancreatic cancer cells

Discovery of a spirocyclic 3-bromo-4,5-dihydroisoxazole covalent inhibitor of hGAPDH with antiproliferative activity against pancreatic cancer cells

  • Eur J Med Chem. 2023 Apr 6;254:115286. doi: 10.1016/j.ejmech.2023.115286.
Andrea Galbiati 1,  Stefania Bova 2,  Raffaella Pacchiana 3,  Chiara Borsari 4,  Marco Persico 5,  Aureliano Zana 1,  Stefano Bruno 6,  Massimo Donadelli 3,  Caterina Fattorusso 5,  Paola Conti 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133, Milano, Italy.
  • 2 Department of Medicine and Surgery, University of Parma, 43125, Parma, Italy.
  • 3 Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134, Verona, Italy.
  • 4 Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133, Milano, Italy; Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland.
  • 5 Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, 80131, Napoli, Italy.
  • 6 Food and Drug Department, University of Parma, 43124, Parma, Italy.
  • 7 Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133, Milano, Italy. Electronic address: [email protected].
PMID: 37058971 DOI: 10.1016/j.ejmech.2023.115286
Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key glycolytic Enzyme, plays a crucial role in the energy metabolism of Cancer cells and has been proposed as a valuable target for the development of Anticancer agents. Among a series of 5-substituted 3-bromo-4,5-dihydroisoxazole (BDHI) derivatives, we identified the spirocyclic compound 11, which is able to covalently inactivate recombinant human GAPDH (hGAPDH) with a faster reactivity than koningic acid, one of the most potent hGAPDH inhibitors known to date. Computational studies confirmed that conformational rigidification is crucial to stabilize the interaction of the inhibitor with the binding site, thus favoring the subsequent covalent bond formation. Investigation of intrinsic warhead reactivity at different pH disclosed the negligible reactivity of 11 with free thiols, highlighting its ability to selectively react with the activated cysteine of hGAPDH with respect to other sulfhydryl groups. Compound 11 strongly reduced Cancer cell growth in four different pancreatic Cancer cell lines and its antiproliferative activity correlated well with the intracellular inhibition of hGAPDH. Overall, our results qualify 11 as a potent hGAPDH covalent inhibitor with a moderate drug-like reactivity that could be further exploited to develop Anticancer agents.

Keywords

3-Bromo-4,5-dihydroisoxazole; Anti-cancer activity; Covalent inhibitor; Glyceraldehyde-3-phosphate dehydrogenase; Glycolysis.

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