2. Academic Validation
  3. HDAC specificity and kinase off-targeting by purine-benzohydroxamate anti-hematological tumor agents

HDAC specificity and kinase off-targeting by purine-benzohydroxamate anti-hematological tumor agents

  • Eur J Med Chem. 2023 Nov 10:263:115935. doi: 10.1016/j.ejmech.2023.115935.
Karoline B Waitman 1,  Larissa C de Almeida 2,  Marina C Primi 3,  Jorge A E G Carlos 2,  Claudia Ruiz 4,  Thales Kronenberger 5,  Stefan Laufer 6,  Marcia Ines Goettert 6,  Antti Poso 5,  Sandra V Vassiliades 1,  Vinícius A M de Souza 1,  Mônica F Z J Toledo 1,  Neuza M A Hassimotto 7,  Michael D Cameron 4,  Thomas D Bannister 4,  Letícia V Costa-Lotufo 2,  João A Machado-Neto 2,  Maurício T Tavares 8,  Roberto Parise-Filho 9
Affiliations

Affiliations

  • 1 Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
  • 2 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, United States.
  • 4 Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, 33458, United States.
  • 5 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-Universität, Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany; Tübingen Center for Academic Drug Discovery & Development (TüCAD(2)), 72076, Tübingen, Germany; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland; Excellence Cluster "Controlling Microbes to Fight Infections" (CMFI), 72076, Tübingen, Germany.
  • 6 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-Universität, Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany; Tübingen Center for Academic Drug Discovery & Development (TüCAD(2)), 72076, Tübingen, Germany.
  • 7 Food Research Center-(FoRC-CEPID) and Department of Food Science and Nutrition, Faculty of Pharmaceutical Science, University of São Paulo, São Paulo, SP, Brazil.
  • 8 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, United States. Electronic address: mauriciot_tavares@dfci.harvard.edu.
  • 9 Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: roberto.parise@usp.br.
PMID: 37989057 DOI: 10.1016/j.ejmech.2023.115935
Abstract

A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The compounds have been synthesized and tested against solid and hematological tumor cell lines. Compounds 4d-f were the most promising in cytotoxicity assays (IC50 ≤ 50 nM) vs. hematological cells and displayed moderate activity in solid tumor models (EC50 = 9.3-21.7 μM). Compound 4d potently inhibited multiple kinase targets of interest for Anticancer effects, including JAK2, JAK3, HDAC1, and HDAC6. Molecular dynamics simulations showed that 4d has stable interactions with HDAC and members of the JAK family, with differences in the hinge binding energy conferring selectivity for JAK3 and JAK2 over JAK1. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t1/2: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms.

Keywords

Anticancer compounds; HDAC inhibitors; Hematological tumors; Hybrid inhibitors; Kinase inhibitors; Molecular dynamics.

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