Identification of a dihydroorotate dehydrogenase inhibitor thatinhibits cancer cell growth by proteomic profiling  

作　　者：MAKOTO KAWATANI HARUMI AONO SAYOKO HIRANUMA TAKESHI SHIMIZU MAKOTO MUROI TOSHIHIKO NOGAWA TOMOKAZU OHISHI SHUN-ICHI OHBA MANABU KAWADA KANAMI YAMAZAKI SHINGO DAN NAOSHI DOHMAE HIROYUKI OSADA 

机构地区：[1]Biomolecular Characterization Unit,Technology Platform Division,RIKEN Center for Sustainable Resource Science(CSRS),Saitama,351-0198,Japan [2]Chemical Resource Development Unit,Technology Platform Division,RIKEN Center for Sustainable Resource Science(CSRS),Saitama,351-0198,Japan [3]Chemical Biology Research Group,RIKEN Center for Sustainable Resource Science(CSRS),Saitama,351-0198,Japan [4]Molecular Structure Characterization Unit,Technology Platform Division,RIKEN Center for Sustainable Resource Science(CSRS),Saitama,351-0198,Japan [5]Institute of Microbial Chemistry(BIKAKEN),Numazu,Microbial Chemistry Research Foundation,Shizuoka,410-0301,Japan [6]Division of Molecular Pharmacology,Cancer Chemotherapy Center,Japan Foundation for Cancer Research,Tokyo,135-8550,Japan [7]Department of Pharmaceutical Sciences,University of Shizuoka,Shizuoka,422-8526,Japan

出　　处：《Oncology Research》2023年第6期833-844,共12页肿瘤学研究（英文）

基　　金：supported by AMED Grants(Nos.JP16cm0106112 and JP16cm0106002);JSPS KAKENHI Grants(Nos.JP17H06412,18H05503,JP19K05744,JP20K05857,JP20H05620,JP21H04720,JP22H04922,and JP22K05363).

摘　　要：Dihydroorotate dehydrogenase(DHODH)is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune diseases.This study presents the identification of a potent DHODH inhibitor by proteomic profiling.Cell-based screening revealed that NPD723,which is reduced to H-006 in cells,strongly induces myeloid differentiation and inhibits cell growth in HL-60 cells.H-006 also suppressed the growth of various cancer cells.Proteomic profiling of NPD723-treated cells in ChemProteoBase showed that NPD723 was clustered with DHODH inhibitors.H-006 potently inhibited human DHODH activity in vitro,whereas NPD723 was approximately 400 times less active than H-006.H-006-induced cell death was rescued by the addition of the DHODH product orotic acid.Moreover,metabolome analysis revealed that H-006 treatment promotes marked accumulation of the DHODH substrate dihydroorotic acid.These results suggest that NPD723 is reduced in cells to its active metabolite H-006,which then targets DHODH and suppresses cancer cell growth.Thus,H-006-related drugs represent a potentially powerful treatment for cancer and other diseases.

关 键 词：Anticancer agents Differentiating agents Drug target identification 

分 类 号：R730[医药卫生—肿瘤]