Discovery of a new class of MTH1 inhibitor by X-ray crystallographic screening

Yokoyama, Takeshi; Kitakami, R.; Mizuguchi, Mineyuki

doi:10.1016/j.ejmech.2019.02.011

Cited by 12 publications

(4 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analogues with a nitrogen atom at the 2-position relative to the amide group (10) improved activity while nitrogen at 3 and 4 positions (11−12) had lower activity, which is consistent with the prior observations for 4−6. The orientation of the ethynyl imidazopyridazine was important, as demonstrated by compound 14 with ethynyl imidazopyrida- zine para to the amide substituent achieving 1600 ± 200% activation at 10 μM and 350 ± 20% at 5 μM, followed by meta (10) and ortho (13). The analogues with a five-membered ring also were active, while 1-methylpyrazole ( 16) with 380 ± 10% activation at 5 μM was better than thiophene (15) and comparable to 14.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…OGG1 excises the mutagenic base in DNA, while MTH1 recognizes the damaged nucleotide 8-oxo-dGTP and cleaves the triphosphate moiety, preventing its incorporation into DNA. Mouse models lacking either MTH1 or OGG1 expression show elevated levels of 8-oxo-dG in DNA and increased tumor risks, which suggests that both enzymes contribute to limiting the amounts of oxidative damage in DNA. ,− Interestingly, some tumor cell lines and solid tumors may upregulate such enzymes to combat growth-limiting cytotoxicity that can arise from high levels of reactive oxygen. , As a result, both enzymes have been under investigation and debate recently as potential antitumor targets, with potent inhibitors of MTH1 and OGG1 reported recently. − …”

mentioning

confidence: 99%

See 1 more Smart Citation

Enhancing Repair of Oxidative DNA Damage with Small-Molecule Activators of MTH1

et al. 2022

View full text Add to dashboard Cite

Impaired DNA repair activity has been shown to greatly increase rates of cancer clinically. It has been hypothesized that upregulating repair activity in susceptible individuals may be a useful strategy for inhibiting tumorigenesis. Here, we report that selected tyrosine kinase (TK) inhibitors including nilotinib, employed clinically in the treatment of chronic myeloid leukemia, are activators of the repair enzyme Human MutT Homolog 1 (MTH1). MTH1 cleanses the oxidatively damaged cellular nucleotide pool by hydrolyzing the oxidized nucleotide 8-oxo-2'-deoxyguanosine (8-oxo-dG)TP, which is a highly mutagenic lesion when incorporated into DNA. Structural optimization of analogues of TK inhibitors resulted in compounds such as SU0448, which induces 1000 ± 100% activation of MTH1 at 10 μM and 410 ± 60% at 5 μM. The compounds are found to increase the activity of the endogenous enzyme, and at least one (SU0448) decreases levels of 8-oxo-dG in cellular DNA. The results suggest the possibility of using MTH1 activators to decrease the frequency of mutagenic nucleotides entering DNA, which may be a promising strategy to suppress tumorigenesis in individuals with elevated cancer risks.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Enhancing Repair of Oxidative DNA Damage with Small-Molecule Activators of MTH1

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The recombinant pET‐22b(+)‐TR‐β (nuclear receptor interaction domain, residues 202–461) synthesized by GenScript, Piscataway, NJ, USA was transformed into E. coli SoluBL21 cells. C‐terminally his‐tagged proteins, each with a 3C protease site, were expressed and purified according to a previous procedure [37]. The protein purity was evaluated by SDS/PAGE with Coomassie brilliant blue staining and yielded a single band, indicating high purity.…”

Section: Methodsmentioning

confidence: 99%

Rafoxanide, a salicylanilide anthelmintic, interacts with human plasma protein transthyretin

et al. 2023

Self Cite

View full text Add to dashboard Cite

Transthyretin (TTR) is a carrier protein for thyroid hormone thyroxine (T4) in plasma, placental cytosol, and cerebrospinal fluid. While the potential toxicity of small molecules that compete with T4 for binding to TTR should be carefully studied, these small molecules can also serve as anti‐ATTR amyloidosis drugs by stabilizing the TTR structure. Here, we demonstrated that rafoxanide, an EU‐approved anthelmintic drug for domesticated animals, binds to the T4‐binding site of TTR. An intrinsic fluorescence quenching assay showed that rafoxanide also binds to the thyroid hormone‐related proteins, including serum albumin and thyroid hormone receptor β. Rafoxanide strongly inhibited TTR amyloidogenesis in fibrillization assay, but the binding of rafoxanide to TTR was interfered with in human plasma, probably due to interactions with thyroid hormone‐related proteins. Protein crystallography provided clues for the optimization of binding affinity and selectivity. Our findings emphasize the importance of considering rafoxanide as both a possible thyroid‐disrupting chemical and a lead compound for the development of new ATTR amyloidosis inhibitors.

show abstract

“…The intrinsic ATPase activities of the kinases were measured by a colorimetric malachite green assay as described previously, with minor modifications (Sherwood et al, 2013;Yokoyama et al, 2019). The protein samples (0.1 mM DAPK1 or 3 mM EphA3) were incubated with the designated concentration of ATP at 298 K for 30-180 min.…”

Section: Intrinsic Atpase Activity Measurementmentioning

confidence: 99%

Crystal structure of death-associated protein kinase 1 in complex with the dietary compound resveratrol

Yokoyama

Suzuki

Mizuguchi

2021

IUCrJ

Self Cite

View full text Add to dashboard Cite

Death-associated protein kinase 1 (DAPK1) is a large multidomain protein with an N-terminal serine/threonine protein kinase domain. DAPK1 is considered to be a promising molecular target for the treatment of Alzheimer's disease (AD). In the present study, the inhibitory potency of resveratrol (RSV), a dietary polyphenol found in red wine, against the catalytic activity of DAPK1 was investigated. Kinetic and fluorescent probe competitive binding analyses revealed that RSV directly inhibited the catalytic activity of DAPK1 by binding to the ATP-binding site. Crystallographic analysis of DAPK1 in complex with RSV revealed that the A-ring of RSV occupied the nucleobase-binding position. Determination of the binding mode provided a structural basis for the design of more potent DAPK1 inhibitors. In conclusion, the data here clearly show that RSV is an ATP-competitive inhibitor of DAPK1, encouraging speculation that RSV may be useful for the development of AD inhibitors.

show abstract

Discovery of a new class of MTH1 inhibitor by X-ray crystallographic screening

Cited by 12 publications

References 41 publications

Enhancing Repair of Oxidative DNA Damage with Small-Molecule Activators of MTH1

Enhancing Repair of Oxidative DNA Damage with Small-Molecule Activators of MTH1

Rafoxanide, a salicylanilide anthelmintic, interacts with human plasma protein transthyretin

Crystal structure of death-associated protein kinase 1 in complex with the dietary compound resveratrol

Contact Info

Product

Resources

About