Dataset Information


Transcriptional study of ARN8 cells treated with novel DHODH inhibitors

ABSTRACT: We have previously observed protein level changes after treating human cells with two novel inhibitors of the enzyme DHODH. This study was designed to study up to what degree these protein differences can be also observed at level of mRNA. As part of the de novo pyrimidine synthesis pathway, DHODH inhibition is expected to decrease the levels of total RNA in cells. However, some effector proteins associated with the p53 pathway are increased after treatment with these inhibitors. This study aims to answer if the observed protein differences are based on an increased transcription or due to protein stabilization. Overall design: The data represent three independent experiments. In each experiment ARN8 cells were treated with two DHODH inhibitors (DrugA and DrugM) and a vehicle control.

INSTRUMENT(S): Illumina NextSeq 500 (Homo sapiens)

SUBMITTER: Vicent Pelechano  

PROVIDER: GSE87577 | GEO | 2018-03-21


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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.

Ladds Marcus J G W MJGW   van Leeuwen Ingeborg M M IMM   Drummond Catherine J CJ   Chu Su S   Healy Alan R AR   Popova Gergana G   Pastor Fernández Andrés A   Mollick Tanzina T   Darekar Suhas S   Sedimbi Saikiran K SK   Nekulova Marta M   Sachweh Marijke C C MCC   Campbell Johanna J   Higgins Maureen M   Tuck Chloe C   Popa Mihaela M   Safont Mireia Mayoral MM   Gelebart Pascal P   Fandalyuk Zinayida Z   Thompson Alastair M AM   Svensson Richard R   Gustavsson Anna-Lena AL   Johansson Lars L   Färnegårdh Katarina K   Yngve Ulrika U   Saleh Aljona A   Haraldsson Martin M   D'Hollander Agathe C A ACA   Franco Marcela M   Zhao Yan Y   Håkansson Maria M   Walse Björn B   Larsson Karin K   Peat Emma M EM   Pelechano Vicent V   Lunec John J   Vojtesek Borivoj B   Carmena Mar M   Earnshaw William C WC   McCarthy Anna R AR   Westwood Nicholas J NJ   Arsenian-Henriksson Marie M   Lane David P DP   Bhatia Ravi R   McCormack Emmet E   Laín Sonia S  

Nature communications 20180316 1

The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is  ...[more]

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