ArticleProceedings of the National Academy of Sciences of the United States of America2018
The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 58 citations in OpenAlex.
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Allosteric targeting with antiviral nucleotide analogs allows fine-tuning of SAMHD1 dNTPase activity.The Journal of biological chemistry · 2026Article
- Enhancing the Nucleoside Analog Response with Translational Therapeutic Approaches to Overcome Resistance.Cells · 2026Review
- Continuous assay for the dNTP triphosphohydrolase of activated SAMHD1.Analytical biochemistry · 2026Article
- Cellular pharmacology of fludarabine: molecular determinants of transport and metabolism.Frontiers in pharmacology · 2026Review
- Addition of hydroxyurea (hydroxycarbamide) enhances the efficacy of fludarabine/cytarabine-based salvage regimens against acute myeloid leukaemia.British journal of haematology · 2025Article
- CDADC1 is a vertebrate-specific dCTP deaminase that metabolizes gemcitabine and decitabine to prevent cellular toxicity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- SAMHD1 dysfunction impairs DNA damage response and increases sensitivity to PARP inhibition in chronic lymphocytic leukemia.Scientific reports · 2025Article
- Inhibitors of SAMHD1 Obtained from Chemical Tethering to the Guanine Antiviral Acyclovir.Biochemistry · 2025Article
- Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis.Nature communications · 2024Article
- 4'-Ethynyl-2'-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress.Molecular cancer therapeutics · 2024Article
- Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1 via a comprehensive screening funnel.iScience · 2024Article
- Deoxyguanosine-Linked Bifunctional Inhibitor of SAMHD1 dNTPase Activity and Nucleic Acid Binding.ACS chemical biology · 2023Article
- SAMHD1 single nucleotide polymorphisms impact outcome in children with newly diagnosed acute myeloid leukemia.Blood advances · 2023Article
- Targeting SAMHD1: To overcome multiple anti-cancer drugs resistance in hematological malignancies.Genes & diseases · 2023Review
- Attenuation of reverse transcriptase facilitates SAMHD1 restriction of HIV-1 in cycling cells.Retrovirology · 2023Article
- Targeting the DNA damage response and repair in cancer through nucleotide metabolism.Molecular oncology · 2022Review
- Review
- Phosphorylation of SAMHD1 Thr592 increases C-terminal domain dynamics, tetramer dissociation and ssDNA binding kinetics.Nucleic acids research · 2022Article
- SAMHD1 in cancer: curse or cure?Journal of molecular medicine (Berlin, Germany) · 2022Review
Corrections and comments
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Authors and funding
15 authors at 6 institutions in 3 countries.
Funding
Abstract
SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in noncycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analog drugs important for treating a variety of cancers, including acute myeloid leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We found that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogs tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer. Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regard to nucleotide analogs, which can be used to improve current cancer and antiviral therapies.
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