Development of a chemical probe against NUDT15.

Nature Chemical Biology
Si Min ZhangThomas Helleday

Abstract

The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.

References

Oct 11, 1996·The Journal of Biological Chemistry·M J BessmanS F O'Handley
Aug 10, 1999·Nature·W C HahnR A Weinberg
Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
May 18, 2001·Best Practice & Research. Clinical Haematology·T BüchnerA Heinecke
May 28, 2003·Biochemical and Biophysical Research Communications·Jian-Ping CaiMutsuo Sekiguchi
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Alexei Vagin, Alexei Teplyakov
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Sep 17, 2011·Journal of Chemical Information and Modeling·Roman A Laskowski, Mark B Swindells
Oct 1, 2011·Methods in Molecular Biology·Oleg FedorovStefan Knapp
Nov 11, 2011·World Journal of Gastroenterology : WJG·Kara Bradford, David Q Shih
Oct 19, 2012·The Journal of Biological Chemistry·Changjun YouYinsheng Wang
Jan 29, 2013·RNA·Man-Gen SongMegerditch Kiledjian
Jun 18, 2014·Journal of Pediatric Hematology/oncology·Kjeld SchmiegelowJacob Nersting
Jul 24, 2014·The FEBS Journal·Gergely N NagyBeáta G Vértessy
Aug 8, 2014·Nature Protocols·Rozbeh JafariDaniel Martinez Molina
Jan 27, 2015·Methods in Molecular Biology·Melody Y PaiJing Huang
Jan 28, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jun J YangMary V Relling
Feb 16, 2016·Nature Genetics·Takaya MoriyamaJun J Yang
Jan 1, 2015·Computational and Structural Biotechnology Journal·Bhagwan YadavJing Tang
Jun 18, 2016·DNA Repair·Sean G RuddThomas Helleday
Aug 18, 2016·Cancer Research·Nicholas C K ValerieThomas Helleday
Aug 25, 2017·Protein Science : a Publication of the Protein Society·Elizabeth JurrusNathan A Baker
Oct 21, 2017·Best Practice & Research. Clinical Haematology·Shawn H R Lee, Jun J Yang
Nov 17, 2017·Nature Communications·Jordi Carreras-PuigvertThomas Helleday
Jan 19, 2018·Nature Communications·Brent D G PageThomas Helleday
Apr 15, 2018·Molecular Cancer Therapeutics·Satarupa SenguptaRachid Drissi
Jul 31, 2019·Molecular Cancer Therapeutics·Takaya MoriyamaJun J Yang
Feb 26, 2020·Proceedings of the National Academy of Sciences of the United States of America·Chase C SuiterJun J Yang

❮ Previous
Next ❯

Citations

Jul 1, 2021·Cell Chemical Biology·Si Min ZhangThomas Helleday

❮ Previous
Next ❯

Methods Mentioned

BETA
GTPase
differential scanning fluorimetry
thermal shift
PCR
protein assay
electrophoresis

Software Mentioned

Ligplot +
GraphPad Prism
Aimless
iMOSFLM
Image Studio
Phenix
SynergyFinder
CCP4
Refine
Phaser

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.