Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

Tatsuro Kawamura, Makoto Kawatani, Makoto Muroi, Yasumitsu Kondoh, Yushi Futamura, Harumi Aono, Miho Tanaka, Kaori Honda, Hiroyuki Osada*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)

Abstract

Since recent publications suggested that the survival of cancer cells depends on MTH1 to avoid incorporation of oxidized nucleotides into the cellular DNA, MTH1 has attracted attention as a potential cancer therapeutic target. In this study, we identified new purine-based MTH1 inhibitors by chemical array screening. However, although the MTH1 inhibitors identified in this study targeted cellular MTH1, they exhibited only weak cytotoxicity against cancer cells compared to recently reported first-in-class inhibitors. We performed proteomic profiling to investigate the modes of action by which chemically distinct MTH1 inhibitors induce cancer cell death, and found mechanistic differences among the first-in-class MTH1 inhibitors. In particular, we identified tubulin as the primary target of TH287 and TH588 responsible for the antitumor effects despite the nanomolar MTH1-inhibitory activity in vitro. Furthermore, overexpression of MTH1 did not rescue cells from MTH1 inhibitor-induced cell death, and siRNA-mediated knockdown of MTH1 did not suppress cancer cell growth. Taken together, we conclude that the cytotoxicity of MTH1 inhibitors is attributable to off-target effects and that MTH1 is not essential for cancer cell survival.

Original languageEnglish
Article number26521
JournalScientific reports
Volume6
DOIs
Publication statusPublished - 2016 May 23
Externally publishedYes

ASJC Scopus subject areas

  • General

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