Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1viaa comprehensive screening funnel DOI Creative Commons
Si Min Zhang, Cynthia B. J. Paulin, Maurice Michel

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 18, 2023

Abstract Sterile alpha motif and histidine-aspartic acid domain containing protein-1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase central to cellular nucleotide pool homeostasis. Recent literature has also demonstrated how SAMHD1 can detoxify chemotherapy metabolites thereby controlling their clinical responses. To further understand biology investigate the potential of targeting this enzyme as neoadjuvant existing chemotherapies we set out discover selective small molecule-based inhibitors SAMHD1. Here report discovery pipeline encompassing biochemical screening campaign complementary biochemical, biophysical, cell-based readouts for characterisation screen output. The identified hit compound TH6342 its analogues, accompanied by inactive negative control analogue TH7126, specific, low μM potency in inhibiting hydrolysis both natural substrates therapeutics, shown using enzyme-coupled direct enzymatic activity assays. Their mode inhibition was subsequently detailed coupling kinetic studies with thermal shift assays, where analogues were engage pre-tetrameric deter oligomerisation allosteric activation without occupying binding pockets. We outline development application multiple assays assessing target engagement associated functional effects, including CETSA an in-cell dNTP hydrolase assay, which highlighted future optimisation strategies chemotype. In summary, novel inhibition, broaden tool compounds available deciphering enzymology functions, furthermore, reported herein represents thorough framework inhibitor development. Figure

Language: Английский

Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1 via a comprehensive screening funnel DOI Creative Commons
Si Min Zhang, Cynthia B. J. Paulin, Huazhang Shu

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(2), P. 108907 - 108907

Published: Jan. 19, 2024

Report a rigorous SAMHD1 chemical probe discovery pipelineIdentified series of low micromolar inhibitors, exemplified by

Language: Английский

Citations

2
A DNA damage-amplifying nanoagent for cancer treatment via two-way regulation of redox dyshomeostasis and downregulation of tetrahydrofolate DOI
Yi Wang,

Zelong Chen,

Xingwang An

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 277, P. 134276 - 134276

Published: Oct. 1, 2024

Language: Английский

Citations

2
Targeting pan-essential pathways in cancer with cytotoxic chemotherapy: challenges and opportunities DOI Creative Commons
Sean G. Rudd

Cancer Chemotherapy and Pharmacology, Journal Year: 2023, Volume and Issue: 92(4), P. 241 - 251

Published: July 15, 2023

Abstract Cytotoxic chemotherapy remains a key modality in cancer treatment. These therapies, successfully used for decades, continue to transform the lives of patients daily. With high attrition rate current oncology drug development, combined with knowledge that most new therapies do not displace standard-of-care treatments and many healthcare systems cannot afford these therapies; cytotoxic chemotherapies will remain an important component therapy years come. The clinical value is often under-appreciated within pre-clinical research community, where this diverse class agents are grouped together as non-specific cellular poisons killing tumor cells based solely upon proliferation rate; however, inaccurate. This review article seeks reaffirm importance focusing efforts improving our basic understanding how drugs work, discussing their ability target pan-essential pathways cells, relationship chemotherapeutic window, highlighting science approaches can be employed towards refining use.

Language: Английский

Citations

6
SAMHD1 restricts the deoxyguanosine triphosphate pool contributing to telomere stability in telomerase‐positive cells DOI Creative Commons

Giulia D'Aronco,

Paola Ferraro,

Valentina Sassano

et al.

The FASEB Journal, Journal Year: 2023, Volume and Issue: 37(4)

Published: March 19, 2023

SAMHD1 (Sterile alpha motif and histidine/aspartic acid domain-containing protein 1) is a dNTP triphosphohydrolase crucial in the maintenance of balanced cellular pools, which support genome integrity. In deficient fibroblasts isolated from Aicardi-Goutières Syndrome (AGS) patients, all four DNA precursors are increased markedly imbalanced with largest effect on dGTP, key player modulation telomerase processivity. Here, we present data showing that SAMHD1, by restricting dGTP pool, contributes to telomere hTERT-immortalized human AGS patients as well positive cancer cell lines. Only cells expressing telomerase, lack causes excessive lengthening telomeres fragility, whereas primary lacking both enter normally into senescence. Telomere observed but proficient gradual process, accordance intrinsic property adding only few tens nucleotides for each cycle. Therefore, prolonged exposure high content over-elongation. display also fragility chromosome ends, marker replication stress. These results not demonstrate functional importance level reveal critical role played restraining processivity safeguarding stability.

Language: Английский

Citations

5
Benzo[a]pyrene-induced up-regulation of circ_0003552 via ALKBH5-mediated m6A modification promotes DNA damage in human bronchial epithelial cells DOI

Shuwei Yao,

Xintong Chen,

Ningdong Hu

et al.

Environmental Pollution, Journal Year: 2023, Volume and Issue: 336, P. 122367 - 122367

Published: Aug. 11, 2023

Language: Английский

Citations

5
Cepharanthine synergizes with photodynamic therapy for boosting ROS-driven DNA damage and suppressing MTH1 as a potential anti-cancer strategy DOI Creative Commons
Ziyi Yang,

Liu‐Gen Li,

Yi-Lian Xiong

et al.

Photodiagnosis and Photodynamic Therapy, Journal Year: 2023, Volume and Issue: 45, P. 103917 - 103917

Published: Nov. 30, 2023

Photodynamic therapy (PDT) primarily treats skin diseases or cancer by generating reactive oxygen species (ROS) to damage cellular DNA, yet drug resistance limits its application. To tackle this problem, the present study was carried out improve efficacy of chlorin e6 (Ce6)-PDT using Cepharanthine (CEP) as well reveal potential molecular mechanism.

Language: Английский

Citations

5
Targeting MutT Homolog 1 (MTH1) for Breast Cancer Suppression by Using a Novel MTH1 Inhibitor MA−24 with Tumor-Selective Toxicity DOI Creative Commons
Nannan Kang, Jun Ma,

Yuling Hu

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(3), P. 291 - 291

Published: Feb. 23, 2024

Breast cancer is a commonly diagnosed worldwide. Human MutT homolog 1 (MTH1) found to be elevated in breast tumors and cells need MTH1 for survival. Pharmacological inhibition of may potentially beneficial the treatment cancer. MA-24 was screened by malachite green colorimetric assay inhibitors kinetic characteristics were assessed. The features MA-24's binding with ascertained through molecular docking, cytotoxic activity validated vitro vivo. Target engagement assays, comet assay, Western blot confirmed intracellular target mechanism MA-24. shows potent antitumor bioactivity both competitively inhibited further induced DNA strand breaks, leading increased apoptosis depending on upregulation cleaved-caspase 3-cleaved-PARP axis. In particular, exhibited powerful efficacy safety vivo (tumor growth rate: 61.8%). possesses broad spectrum cytotoxicity offered valuable insights overcoming challenges chemotherapy-related toxicity, which holds great potential development as an anti-cancer drug.

Language: Английский

Citations

1
Characterization of tumor immune microenvironment and cancer therapy for head and neck squamous cell carcinoma through identification of a genomic instability-related lncRNA prognostic signature DOI Creative Commons

Lijun Jing,

Yabing Du,

Denggang Fu

et al.

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 29, 2022

Head and neck squamous cell carcinoma (HNSCC) represents one of the most prevalent malignant tumors epithelial origins with unfavorable outcomes. Increasing evidence has shown that dysregulated long non-coding RNAs (lncRNAs) correlate tumorigenesis genomic instability (GI), while roles GI-related lncRNAs in tumor immune microenvironment (TIME) predicting cancer therapy are still yet to be clarified. In this study, transcriptome somatic mutation profiles clinical parameters were obtained from TCGA database. Patients classified into GI-like stable (GS)-like groups according top 25% bottom cumulative counts mutations. Differentially expressed (DElncRNAs) between GI- GS-like identified as lncRNAs. These lncRNA-related coding genes enriched cancer-related KEGG pathways. totaling 499 information randomly divided training validation sets. A total 18 DElncRNAs screened by univariate Cox regression analysis associated overall survival (OS) set. lncRNA signature comprised 10 was generated through least absolute shrinkage selection operator (Lasso)-Cox analysis. high-risk group have significantly decreased OS vs. patients low-risk group, which verified internal entire HNSCC Integrated sets GEO confirmed notable stratification signature. The time-dependent receiver operating characteristic curve demonstrated reliable. addition, retained a strong performance prediction for various clinicopathological features. Cell composition showed high anti-tumor immunity evidenced increased infiltrating CD8+ T cells natural killer reduced cancer-associated fibroblasts, convinced signatures via ssGSEA algorithm. helper/IFNγ signaling, co-stimulatory, co-inhibitory expression group. Low-risk predicted beneficial immunotherapy, progressive disease who had risk scores complete remission patients. Furthermore, drugs might sensitive identified. summary, novel prognostic GILncRNA provided promising approach characterizing TIME therapeutic strategies

Language: Английский

Citations

6
Protonation states of Asp residues in the human Nudix hydrolase MTH1 contribute to its broad substrate recognition DOI
Teruya Nakamura,

YUKARI KOGA-OGAWA,

Kana Fujimiya

et al.

FEBS Letters, Journal Year: 2023, Volume and Issue: 597(13), P. 1770 - 1778

Published: March 14, 2023

Human MutT homolog 1 (MTH1), also known as Nudix-type motif (NUDT1), hydrolyzes 8-oxo-dGTP and 2-oxo-dATP with broad substrate recognition has attracted attention in anticancer therapeutics. Previous studies on MTH1 have proposed that the exchange of protonation state between Asp119 Asp120 is essential for MTH1. To understand relationship states binding, we determined crystal structures at pH 7.7-9.7. With increasing pH, gradually loses its substrate-binding ability, indicating deprotonated 8.0-9.1 8.6-9.7 recognition. These results confirm recognizes by exchanging higher pKa .

Language: Английский

Citations

2
Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity DOI Open Access
Nannan Kang,

Jun Ma,

Yuling Hu

et al.

Published: Dec. 21, 2023

Background: Breast cancer is a commonly diagnosed worldwide. Human MutT homolog 1 (MTH1) found to be elevated in breast tumors and cells are addicted MTH1 for sur-vival. Pharmacological inhibition of may potentially beneficial the treatment cancer. Methods: MA-24 was screened by malachite green colorimetric assay from inhibitors kinetic characteristics assessed. Binding features with as-certained through molecular docking, cytotoxic activity validated vitro vivo. Target engagement assays, comet western blot confirmed that intracellular target mechanism MA-24. Results: potent antitumor bioactivity both competitively inhibited further induce DNA strand breaks, leading increased apoptosis depending on upregulation cleaved-caspase 3 – cleaved-PARP axis. Especially, exhibited powerful efficacy safety vivo (tumor growth rate: 61.8%). Conclusions: possesses broad spectrum cytotoxicity offered valuable insights overcoming challenges chemotherapy-related toxicity, which holds great po-tential development as an anti-cancer drug.

Language: Английский

Citations

2