TH5427

Inhibitor of NUDT5

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(0 ratings)

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Probe TH5427 is in the process of SERP review.

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Information

NUDT5

Inhibitor

up to 1.5 uM

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Probe Availability:

TOCRIS

In Vitro Validations

Uniprot ID: Q9UKK9

Target Class: Epigenetic

Target SubClass: Nudix Hydrolase

Potency: IC50

Potency Value: 29 nM

Potency Assay: MG assay

PDB ID for probe-target interaction (3D structure): 5NWH

Structure-activity relationship: yes

Target aliases:

ADP-sugar pyrophosphatase, NUDIX5, NUDT5, NUDT5_HU ...

DOI Reference: 10.1038/s41467-017-02293-7

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

Screened in a panel of NUDIX enzymes and other nucleotide phosphohydrolases: outside of NUDT5, had the strongest activity against MTH1 (82 % inhibition) and gave 39, 66, and 38 % inhibition against dCTPase, NUDT12 and NUDT14, respectively, at 100 µM

Probe Selectivity in Cell:

SafetyScreen 44 and ExpresSDiversity kinase panels from Eurofins Cerep Panlabs.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

TH5427 is potent and selective chemical probe for NUDT5, a NUDIX hydrolase enzyme that plays important roles in the metabolism of adenosine-5’-diphisphoribose (ADPR) metabolism and regulation of hormone signaling. NUDT5 has been implicated in breast cancer, and TH5427 should provide a valuable tool for the continued exploration of the role of this target in breast cancer and other diseases models. TH5427 is at least 690-fold selective for NUDT5 over other NUDIX hydrolases in vitro, with only limited demonstrated interactions outside of the NUDIX hydrolyase family. I recommend the use of this probe in cells at concentrations up to 1.5 µM, with demonstrated effectiveness in HL-60 and T47D cells. TH5427 does show a large cellular potency offset comparing potency in vitro (malachite green assay, 29 nm) vs in cellular target engagement assays (CETSA and DARTS, 0.75-2.1 µM), though this potency offset has not been specifically explained (i.e. cellular availability vs metabolite competition or other factors).

(last updated: 11 Jul 2020 )

SERP Ratings

In Cell Rating

SERP Comments:

TH5427 showed 690-fold selectivity for NUDT5 over MTH1 in direct assay of ADP-ribose hydrolysis in vitro.

(last updated: 26 Jul 2020 )