title: Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival.
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.
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawatani
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Muroi
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Futamura
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Aono
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Honda
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D011743:Pyrimidines / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D054852:Small Molecule Libraries; C588302:TH287 compound; C588303:TH588 compound; D014404:Tubulin; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes