First-in-class inhibitors of the ribosomal oxygenase MINA53

Radosław P. Nowak; Anthony Tumber; Eline Hendrix; Mohammad Salik Zeya Ansari; Manuela Sabatino; Lorenzo Antonini; Regina Andrijes; Eidarus Salah; Nicola Mautone; Francesca Romana Pellegrini; Klemensas Simelis; Akane Kawamura; Catrine Johansson; Daniela Passeri; Roberto Pellicciari; Alessia Ciogli; Donatella Del Bufalo; Rino Ragno; Mathew L. Coleman; Daniela Trisciuoglio; Antonello Mai; Udo Oppermann; Christopher J. Schofield; Dante Rotili

doi:10.1021/acs.jmedchem.1c00605

First-in-class inhibitors of the ribosomal oxygenase MINA53

Radosław P. Nowak, Anthony Tumber, Eline Hendrix, Mohammad Salik Zeya Ansari, Manuela Sabatino, Lorenzo Antonini, Regina Andrijes, Eidarus Salah, Nicola Mautone, Francesca Romana Pellegrini, Klemensas Simelis, Akane Kawamura, Catrine Johansson, Daniela Passeri, Roberto Pellicciari, Alessia Ciogli, Donatella Del Bufalo, Rino Ragno, Mathew L. Coleman, Daniela TrisciuoglioAntonello Mai, Udo Oppermann^*, Christopher J. Schofield, Dante Rotili

^*Corresponding author for this work

Cancer and Genomic Sciences

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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.

Original language	English
Pages (from-to)	17031-17050
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	23
Early online date	29 Nov 2021
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00605
Publication status	Published - 9 Dec 2021

Bibliographical note

Funding Information:
Studies were supported by PRIN 2016 (prot. 20152TE5PK) (A.M.), AIRC 2016 (n. 19162) (A.M.), AIRC 2020 (n. 24942) (D.T.), “Sapienza” University Grant 2017 n. RM11715C7CA6CE53 (D.R.), Regione Lazio PROGETTI DI GRUPPI DI RICERCA 2020─A0375-2020-36597 (D.R., D.T.), Cancer Research UK (A23900, U.O., C33483/A25674, M.L.C., and C8717/A18245, C.J.S.), Arthritis Research UK (program grant 205222, U.O.), the Leducq Foundation (LEAN program grant, U.O.), and the Wellcome Trust. This research was funded in whole, or in part, by the Wellcome Trust [Grant number 106244/Z/14/Z]. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, Merck & Co., the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation–FAPESP, Takeda, and the Wellcome Trust (092809/Z/10/Z). We thank Diamond Light Source for beamtime (proposal mx10619) and the staff of beamlines I03 for assistance with crystal testing and data collection.

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Nowak, R. P., Tumber, A., Hendrix, E., Ansari, M. S. Z., Sabatino, M., Antonini, L., Andrijes, R., Salah, E., Mautone, N., Pellegrini, F. R., Simelis, K., Kawamura, A., Johansson, C., Passeri, D., Pellicciari, R., Ciogli, A., Del Bufalo, D., Ragno, R., Coleman, M. L., ... Rotili, D. (2021). First-in-class inhibitors of the ribosomal oxygenase MINA53. Journal of Medicinal Chemistry, 64(23), 17031-17050. Advance online publication. https://doi.org/10.1021/acs.jmedchem.1c00605

@article{e6cc4f5989014ebb8556235d22d772f5,

title = "First-in-class inhibitors of the ribosomal oxygenase MINA53",

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.",

author = "Nowak, {Rados{\l}aw P.} and Anthony Tumber and Eline Hendrix and Ansari, {Mohammad Salik Zeya} and Manuela Sabatino and Lorenzo Antonini and Regina Andrijes and Eidarus Salah and Nicola Mautone and Pellegrini, {Francesca Romana} and Klemensas Simelis and Akane Kawamura and Catrine Johansson and Daniela Passeri and Roberto Pellicciari and Alessia Ciogli and {Del Bufalo}, Donatella and Rino Ragno and Coleman, {Mathew L.} and Daniela Trisciuoglio and Antonello Mai and Udo Oppermann and Schofield, {Christopher J.} and Dante Rotili",

note = "Funding Information: Studies were supported by PRIN 2016 (prot. 20152TE5PK) (A.M.), AIRC 2016 (n. 19162) (A.M.), AIRC 2020 (n. 24942) (D.T.), “Sapienza” University Grant 2017 n. RM11715C7CA6CE53 (D.R.), Regione Lazio PROGETTI DI GRUPPI DI RICERCA 2020─A0375-2020-36597 (D.R., D.T.), Cancer Research UK (A23900, U.O., C33483/A25674, M.L.C., and C8717/A18245, C.J.S.), Arthritis Research UK (program grant 205222, U.O.), the Leducq Foundation (LEAN program grant, U.O.), and the Wellcome Trust. This research was funded in whole, or in part, by the Wellcome Trust [Grant number 106244/Z/14/Z]. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, Merck & Co., the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, S{\~a}o Paulo Research Foundation–FAPESP, Takeda, and the Wellcome Trust (092809/Z/10/Z). We thank Diamond Light Source for beamtime (proposal mx10619) and the staff of beamlines I03 for assistance with crystal testing and data collection.",

year = "2021",

month = dec,

day = "9",

doi = "10.1021/acs.jmedchem.1c00605",

language = "English",

volume = "64",

pages = "17031--17050",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "23",

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Nowak, RP, Tumber, A, Hendrix, E, Ansari, MSZ, Sabatino, M, Antonini, L, Andrijes, R, Salah, E, Mautone, N, Pellegrini, FR, Simelis, K, Kawamura, A, Johansson, C, Passeri, D, Pellicciari, R, Ciogli, A, Del Bufalo, D, Ragno, R, Coleman, ML, Trisciuoglio, D, Mai, A, Oppermann, U, Schofield, CJ & Rotili, D 2021, 'First-in-class inhibitors of the ribosomal oxygenase MINA53', Journal of Medicinal Chemistry, vol. 64, no. 23, pp. 17031-17050. https://doi.org/10.1021/acs.jmedchem.1c00605

TY - JOUR

T1 - First-in-class inhibitors of the ribosomal oxygenase MINA53

AU - Nowak, Radosław P.

AU - Tumber, Anthony

AU - Hendrix, Eline

AU - Ansari, Mohammad Salik Zeya

AU - Sabatino, Manuela

AU - Antonini, Lorenzo

AU - Andrijes, Regina

AU - Salah, Eidarus

AU - Mautone, Nicola

AU - Pellegrini, Francesca Romana

AU - Simelis, Klemensas

AU - Kawamura, Akane

AU - Johansson, Catrine

AU - Passeri, Daniela

AU - Pellicciari, Roberto

AU - Ciogli, Alessia

AU - Del Bufalo, Donatella

AU - Ragno, Rino

AU - Coleman, Mathew L.

AU - Trisciuoglio, Daniela

AU - Mai, Antonello

AU - Oppermann, Udo

AU - Schofield, Christopher J.

AU - Rotili, Dante

N1 - Funding Information: Studies were supported by PRIN 2016 (prot. 20152TE5PK) (A.M.), AIRC 2016 (n. 19162) (A.M.), AIRC 2020 (n. 24942) (D.T.), “Sapienza” University Grant 2017 n. RM11715C7CA6CE53 (D.R.), Regione Lazio PROGETTI DI GRUPPI DI RICERCA 2020─A0375-2020-36597 (D.R., D.T.), Cancer Research UK (A23900, U.O., C33483/A25674, M.L.C., and C8717/A18245, C.J.S.), Arthritis Research UK (program grant 205222, U.O.), the Leducq Foundation (LEAN program grant, U.O.), and the Wellcome Trust. This research was funded in whole, or in part, by the Wellcome Trust [Grant number 106244/Z/14/Z]. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, Merck & Co., the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation–FAPESP, Takeda, and the Wellcome Trust (092809/Z/10/Z). We thank Diamond Light Source for beamtime (proposal mx10619) and the staff of beamlines I03 for assistance with crystal testing and data collection.

PY - 2021/12/9

Y1 - 2021/12/9

N2 - 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.

AB - 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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U2 - 10.1021/acs.jmedchem.1c00605

DO - 10.1021/acs.jmedchem.1c00605

M3 - Article

C2 - 34843649

AN - SCOPUS:85120646873

SN - 0022-2623

VL - 64

SP - 17031

EP - 17050

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 23

ER -

First-in-class inhibitors of the ribosomal oxygenase MINA53

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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