First-in-Class Inhibitors of the Ribosomal Oxygenase MINA53,Journal of Medicinal Chemistry

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First-in-Class Inhibitors of the Ribosomal Oxygenase MINA53
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-29 , 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

Affiliation

Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, Headington OX3 7LD, U.K.
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.
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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.
Rome Center for Molecular Design, Department of Chemistry and Technology of Drugs, ″Sapienza″ University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy.
Department of Chemistry and Technology of Drugs, ″Sapienza″ University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy.
Chemistry - School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
TES Pharma S.r.l. Via P. Togliatti 20, Corciano, Perugia 06073, Italy.
Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.

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.

中文翻译：

一流的核糖体加氧酶 MINA53 抑制剂

MINA53 是一种 JmjC 结构域 2-氧化戊二酸依赖性加氧酶，可催化核糖体羟基化，并且是致癌转录因子c -MYC 的靶标。尽管具有抗癌靶点潜力，但尚未报道小分子 MINA53 抑制剂。使用核糖体底物片段，我们开发了 MINA53 和相关加氧酶 NO66 的质谱分析方法。这些测定能够将 2-(芳基)烷硫基-3,4-二氢-4-氧代嘧啶-5-羧酸鉴定为有效的 MINA53 抑制剂，其选择性优于 NO66 和其他 JmjC 加氧酶。使用 JmjC 去甲基酶 KDM5B 进行的晶体学研究揭示了活性位点结合，但没有直接的金属螯合；然而，分子模型研究表明，抑制剂通过直接与铁辅助因子相互作用来与 MINA53 结合。 MINA53 抑制剂显示了 MINA53 相对于 KDM4-6 的靶点参与和选择性的证据。 MINA53 抑制剂对实体癌细胞系表现出抗增殖活性，并使癌细胞对传统化疗敏感，这表明有必要进一步研究其在联合疗法中的潜力。

更新日期：2021-12-09

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