title: Prolyl-tRNA synthetase inhibition promotes cell death in SK-MEL-2 cells through GCN2-ATF4 pathway activation.
abstract: Protein translation is highly activated in cancer tissues through oncogenic mutations and amplifications, and this can support survival and aberrant proliferation. Therefore, blocking translation could be a promising way to block cancer progression. The process of charging a cognate amino acid to tRNA, a crucial step in protein synthesis, is mediated by tRNA synthetases such as prolyl tRNA synthetase (PRS). Interestingly, unlike pan-translation inhibitors, we demonstrated that a novel small molecule PRS inhibitor (T-3861174) induced cell death in several tumor cell lines including SK-MEL-2 without complete suppression of translation. Additionally, our findings indicated that T-3861174-induced cell death was caused by activation of the GCN2-ATF4 pathway. Furthermore, the PRS inhibitor exhibited significant anti-tumor activity in several xenograft models without severe body weight losses. These results indicate that PRS is a druggable target, and suggest that T-3861174 is a potential therapeutic agent for cancer therapy.
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: takeo.arita@takeda.com.
authors.forename: Takeo
authors.initials: T
authors.lastname: Arita
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: megumi.morimoto@takeda.com.
authors.forename: Megumi
authors.initials: M
authors.lastname: Morimoto
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyashita
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kitazawa
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Hirayama
authors.affiliation: Integrated Technology Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Sou
authors.initials: S
authors.lastname: Sakamoto
authors.affiliation: Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Adachi
authors.affiliation: Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Iwatani
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: takahito.hara@takeda.com.
authors.forename: Takahito
authors.initials: T
authors.lastname: Hara
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010848:Picolinic Acids; D011760:Pyrrolidinones; C000622962:T-3861174; D051701:Activating Transcription Factor 4; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; D000604:Amino Acyl-tRNA Synthetases; C100134:prolyl T RNA synthetase
keywords: CHOP; GCN2-ATF4; Prolyl tRNA synthetase; Translation; tRNA synthetase