2018
DOI: 10.1101/296624
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The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

Abstract: Abstract:SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in non-cycling 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 analogue drugs important for treating a variety of cancers, inc… Show more

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“…Purine nucleoside analogues are clinically combined with ara‐C. Some have also been shown to be substrates/activators of SAMHD1 (Arnold et al , ; Herold et al , ; Hollenbaugh et al , ; Knecht et al , ) and, importantly, are documented to allosterically inhibit RNR as part of their cytotoxic mechanism (Aye & Stubbe, ; Wisitpitthaya et al , ). We thus tested clofarabine (Cl‐F‐ara‐A), fludarabine (2‐F‐ara‐A) and cladribine (2‐CdA) for their ability to synergise with ara‐C.…”
Section: Resultsmentioning
confidence: 99%
“…Purine nucleoside analogues are clinically combined with ara‐C. Some have also been shown to be substrates/activators of SAMHD1 (Arnold et al , ; Herold et al , ; Hollenbaugh et al , ; Knecht et al , ) and, importantly, are documented to allosterically inhibit RNR as part of their cytotoxic mechanism (Aye & Stubbe, ; Wisitpitthaya et al , ). We thus tested clofarabine (Cl‐F‐ara‐A), fludarabine (2‐F‐ara‐A) and cladribine (2‐CdA) for their ability to synergise with ara‐C.…”
Section: Resultsmentioning
confidence: 99%