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Targeted Cancer Therapies

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Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation.

Julie Farand¹, Jeffrey E Kropf², Peter Blomgren²

¹Gilead Sciences, Inc. 333 Lakeside Drive, Foster City, California 94404, United States.

ACS Medicinal Chemistry Letters

|March 19, 2020

Summary

Researchers discovered potent MTH1 inhibitors to test MTH1 as an oncology target. Despite identifying effective compounds, the study found insufficient evidence to validate MTH1 for cancer treatment, thus (in)validating the target.

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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

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Area of Science:

Medicinal Chemistry
Oncology
Molecular Biology

Background:

MTH1 (NUDT1) hydrolyzes oxidized nucleoside triphosphates, preventing DNA damage.
MTH1 has been proposed as a potential oncology target due to its role in maintaining genomic stability.

Purpose of the Study:

To discover and characterize novel MTH1 inhibitors.
To investigate the therapeutic potential of MTH1 inhibition in cancer.
To validate or invalidate MTH1 as a viable oncology target.

Main Methods:

Synthesis and characterization of novel MTH1 inhibitors (compounds 5, 25, and 32).
Cocrystallization of inhibitor 5 with MTH1 to elucidate binding mode.
In vitro assays to assess enzyme inhibition, DNA damage response, cell viability, and intracellular oxo-NTP levels.
Pharmacokinetic studies of lead compound 32 in rats.

Main Results:

Discovery of three potent and selective MTH1 inhibitors: tetrahydronaphthyridine 5 (IC50 = 0.043 nM), pyrimidine-2,4,6-triamine 25 (IC50 = 0.49 nM), and triazolopyridine 32.
Cocrystallography revealed key interactions of inhibitor 5 with MTH1 residues Gly34 and Asp120.
Inhibition of MTH1 led to DNA damage response and reduced cell viability in some contexts.
Compound 32 exhibited favorable in vitro and pharmacokinetic profiles.
However, the study failed to provide conclusive evidence supporting MTH1 as an oncology target.

Conclusions:

Potent MTH1 inhibitors were successfully developed, enabling investigation of MTH1's role in cancer.
The study did not yield sufficient evidence to validate MTH1 as a promising oncology target.
Further research into MTH1's therapeutic utility in oncology is not recommended based on these findings.