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First-in-class inhibitors of the ribosomal oxygenase MINA53

DOI: 10.1021/acs.jmedchem.1c00605 DOI Help

Authors: Radoslaw Nowak (University of Oxford) , Anthony Tumber (University of Oxford) , Eline Hendrix (University of Birmingham) , Mohammad Salik Zeya Ansari (Sapienza″ University of Rome) , Manuela Sabatino (Sapienza″ University of Rome) , Lorenzo Antonini (Sapienza″ University of Rome) , Regina Andrijes (University of Birmingham) , Eidarus Salah (University of Oxford) , Nicola Mautone (″Sapienza″ University of Rome) , Francesca Romana Pellegrini (″Sapienza″ University of Rome) , Klemensas Simelis (University of Oxford) , Akane Kawamura (Newcastle University) , Catrine Johansson (University of Oxford) , Daniela Passeri (TES Pharma S.r.l.) , Roberto Pellicciari (TES Pharma S.r.l.) , Alessia Ciogli (″Sapienza″ University of Rome) , Donatella Del Bufalo (IRCCS-Regina Elena National Cancer Institute) , Rino Ragno (Sapienza″ University of Rome) , Mathew L. Coleman (University of Birmingham) , Daniela Trisciuoglio (Sapienza″ University of Rome) , Antonello Mai (Sapienza″ University of Rome) , Udo Oppermann (University of Oxford) , Christopher J. Schofield (University of Oxford) , Dante Rotili (″Sapienza″ University of Rome)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 1091

State: Published (Approved)
Published: November 2021
Diamond Proposal Number(s): 10619

Open Access Open Access

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.

Journal Keywords: Cells; Inhibitors; Inhibition; Peptides and proteins; Pyrimidine

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 02/12/2021 09:22


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)