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Identification and structure–activity relationship of purine derivatives as novel MTH 1 inhibitors
Author(s) -
Kumar Ashutosh,
Kawamura Tatsuro,
Kawatani Makoto,
Osada Hiroyuki,
Zhang Kam Y. J.
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12909
Subject(s) - purine , biochemistry , enzyme , purine metabolism , cancer cell , docking (animal) , chemistry , dna , nucleotide , cell culture , biology , cancer , gene , genetics , medicine , nursing
The human mutT homolog‐1 ( MTH 1) protein prevents the incorporation of oxidized nucleotides such as 2‐ OH ‐ dATP and 8‐oxo‐ dGTP during DNA 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 MTH 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 MTH 1 inhibitors may be related to their engagement of off‐targets. We have previously reported a few purine‐based MTH 1 inhibitors that enabled us to elucidate the dispensability of MTH 1 in cancer cell survival. Here, we provide a detailed process of the identification of purine‐based MTH 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 MTH 1 inhibitors.