2. Academic Validation
  3. First-in-Class Inhibitors of the Ribosomal Oxygenase MINA53

First-in-Class Inhibitors of the Ribosomal Oxygenase MINA53

  • J Med Chem. 2021 Dec 9;64(23):17031-17050. doi: 10.1021/acs.jmedchem.1c00605.
Radosław P Nowak 1,  Anthony Tumber 1 2,  Eline Hendrix 3,  Mohammad Salik Zeya Ansari 4,  Manuela Sabatino 5,  Lorenzo Antonini 5,  Regina Andrijes 3,  Eidarus Salah 2,  Nicola Mautone 6,  Francesca Romana Pellegrini 4,  Klemensas Simelis 2,  Akane Kawamura 7,  Catrine Johansson 1 2,  Daniela Passeri 8,  Roberto Pellicciari 8,  Alessia Ciogli 6,  Donatella Del Bufalo 9,  Rino Ragno 5,  Mathew L Coleman 3,  Daniela Trisciuoglio 4,  Antonello Mai 6,  Udo Oppermann 1,  Christopher J Schofield 2,  Dante Rotili 6
Affiliations

Affiliations

  • 1 Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, Headington OX3 7LD, U.K.
  • 2 Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, 12, Mansfield Road, University of Oxford, Oxford OX1 3TA, U.K.
  • 3 Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
  • 4 Institute of Molecular Biology and Pathology (IMBP), National Research Council (CNR) c/o Department of Biology and Biotechnology "Charles Darwin" Sapienza University of Rome, Via degli Apuli 4, Rome 00185, Italy.
  • 5 Rome Center for Molecular Design, Department of Chemistry and Technology of Drugs, ″Sapienza″ University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy.
  • 6 Department of Chemistry and Technology of Drugs, ″Sapienza″ University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy.
  • 7 Chemistry - School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
  • 8 TES Pharma S.r.l. Via P. Togliatti 20, Corciano, Perugia 06073, Italy.
  • 9 Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
PMID: 34843649 DOI: 10.1021/acs.jmedchem.1c00605
Abstract

MINA53 is a JmjC domain 2-oxoglutarate-dependent oxygenase that catalyzes ribosomal hydroxylation and is a target of the oncogenic transcription factor c-MYC. Despite its Anticancer target potential, no small-molecule MINA53 inhibitors are reported. Using ribosomal substrate fragments, we developed mass spectrometry assays for MINA53 and the related oxygenase NO66. These assays enabled the identification of 2-(aryl)alkylthio-3,4-dihydro-4-oxoypyrimidine-5-carboxylic acids as potent MINA53 inhibitors, with selectivity over NO66 and Other JmjC oxygenases. Crystallographic studies with the JmjC demethylase KDM5B revealed active site binding but without direct metal chelation; however, molecular modeling investigations indicated that the inhibitors bind to MINA53 by directly interacting with the iron cofactor. The MINA53 inhibitors manifest evidence for target engagement and selectivity for MINA53 over KDM4-6. The MINA53 inhibitors show antiproliferative activity with solid Cancer lines and sensitize Cancer cells to conventional chemotherapy, suggesting that further work investigating their potential in combination therapies is warranted.

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