First-in-class inhibitors of the ribosomal oxygenase MINA53
MINA53 is a JmjC domain 2-oxoglutarate dependent oxygenase that catalyzes ribosomal hydroxylation and which 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 deve...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2021
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| _version_ | 1797069813594456064 |
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| author | Nowak, R Tumber, A Hendrix, E Ansari, M Sabatino, M Antonini, L Andrijes, R Salah, E Mautone, N Pellegrini, F Simelis, K Kawamura, A Johansson, C Passeri, D Pellicciari, R Ciogli, A Del Bufalo, D Ragno, R Coleman, M Trisciuoglio, D Mai, A Oppermann, U Schofield, C Rotili, D |
| author_facet | Nowak, R Tumber, A Hendrix, E Ansari, M Sabatino, M Antonini, L Andrijes, R Salah, E Mautone, N Pellegrini, F Simelis, K Kawamura, A Johansson, C Passeri, D Pellicciari, R Ciogli, A Del Bufalo, D Ragno, R Coleman, M Trisciuoglio, D Mai, A Oppermann, U Schofield, C Rotili, D |
| author_sort | Nowak, R |
| collection | OXFORD |
| description | MINA53 is a JmjC domain 2-oxoglutarate dependent oxygenase that catalyzes ribosomal
hydroxylation and which 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 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
indicate 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 further work investigating their
potential in combination therapies is warranted. |
| first_indexed | 2024-03-06T22:30:00Z |
| format | Journal article |
| id | oxford-uuid:57f7bc10-b0c2-4dbc-a213-ee54809636ec |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:30:00Z |
| publishDate | 2021 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:57f7bc10-b0c2-4dbc-a213-ee54809636ec2022-03-26T17:00:07ZFirst-in-class inhibitors of the ribosomal oxygenase MINA53Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:57f7bc10-b0c2-4dbc-a213-ee54809636ecEnglishSymplectic ElementsAmerican Chemical Society2021Nowak, RTumber, AHendrix, EAnsari, MSabatino, MAntonini, LAndrijes, RSalah, EMautone, NPellegrini, FSimelis, KKawamura, AJohansson, CPasseri, DPellicciari, RCiogli, ADel Bufalo, DRagno, RColeman, MTrisciuoglio, DMai, AOppermann, USchofield, CRotili, DMINA53 is a JmjC domain 2-oxoglutarate dependent oxygenase that catalyzes ribosomal hydroxylation and which 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 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 indicate 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 further work investigating their potential in combination therapies is warranted. |
| spellingShingle | Nowak, R Tumber, A Hendrix, E Ansari, M Sabatino, M Antonini, L Andrijes, R Salah, E Mautone, N Pellegrini, F Simelis, K Kawamura, A Johansson, C Passeri, D Pellicciari, R Ciogli, A Del Bufalo, D Ragno, R Coleman, M Trisciuoglio, D Mai, A Oppermann, U Schofield, C Rotili, D First-in-class inhibitors of the ribosomal oxygenase MINA53 |
| title | First-in-class inhibitors of the ribosomal oxygenase MINA53 |
| title_full | First-in-class inhibitors of the ribosomal oxygenase MINA53 |
| title_fullStr | First-in-class inhibitors of the ribosomal oxygenase MINA53 |
| title_full_unstemmed | First-in-class inhibitors of the ribosomal oxygenase MINA53 |
| title_short | First-in-class inhibitors of the ribosomal oxygenase MINA53 |
| title_sort | first in class inhibitors of the ribosomal oxygenase mina53 |
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