Identification and structure–activity relationship of purine derivatives as novel <scp>MTH</scp>1 inhibitors

DOI Web Site Web Site 被引用文献1件 参考文献38件
  • Ashutosh Kumar
    Structural Bioinformatics Team RIKEN Center for Life Science Technologies Yokohama Kanagawa Japan
  • Tatsuro Kawamura
    Chemical Biology Research Group RIKEN Center for Sustainable Resource Science Wako Saitama Japan
  • Makoto Kawatani
    Chemical Biology Research Group RIKEN Center for Sustainable Resource Science Wako Saitama Japan
  • Hiroyuki Osada
    Chemical Biology Research Group RIKEN Center for Sustainable Resource Science Wako Saitama Japan
  • Kam Y. J. Zhang
    Structural Bioinformatics Team RIKEN Center for Life Science Technologies Yokohama Kanagawa Japan

書誌事項

公開日
2016-12-07
資源種別
journal article
権利情報
  • http://onlinelibrary.wiley.com/termsAndConditions#vor
DOI
  • 10.1111/cbdd.12909
公開者
Wiley

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説明

<jats:p>The human mutT homolog‐1 (<jats:styled-content style="fixed-case">MTH</jats:styled-content>1) protein prevents the incorporation of oxidized nucleotides such as 2‐<jats:styled-content style="fixed-case">OH</jats:styled-content>‐<jats:styled-content style="fixed-case">dATP</jats:styled-content> and 8‐oxo‐<jats:styled-content style="fixed-case">dGTP</jats:styled-content> during <jats:styled-content style="fixed-case">DNA</jats:styled-content> replication by hydrolyzing them into their corresponding monophosphates. It was found previously that cancer cells could tolerate oxidative stress due to this enzymatic activity of <jats:styled-content style="fixed-case">MTH</jats:styled-content>1 and its inhibition could be a promising approach to treat several types of cancer. This finding has been challenged recently with increasing line of evidence suggesting that the cancer cell‐killing effects of <jats:styled-content style="fixed-case">MTH</jats:styled-content>1 inhibitors may be related to their engagement of off‐targets. We have previously reported a few purine‐based <jats:styled-content style="fixed-case">MTH</jats:styled-content>1 inhibitors that enabled us to elucidate the dispensability of <jats:styled-content style="fixed-case">MTH</jats:styled-content>1 in cancer cell survival. Here, we provide a detailed process of the identification of purine‐based <jats:styled-content style="fixed-case">MTH</jats:styled-content>1 inhibitors. Several new compounds with potency in the submicromolar range are disclosed. Furthermore, the structure–activity relationship and associated binding mode prediction using molecular docking have provided insights for the development of highly potent <jats:styled-content style="fixed-case">MTH</jats:styled-content>1 inhibitors.</jats:p>

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