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ARTICLE

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

MAKOTO KAWATANI^1,2,*, HARUMI AONO², SAYOKO HIRANUMA³, TAKESHI SHIMIZU³, MAKOTO MUROI^1,2, TOSHIHIKO NOGAWA⁴, TOMOKAZU OHISHI⁵, SHUN-ICHI OHBA⁵, MANABU KAWADA⁵, KANAMI YAMAZAKI⁶, SHINGO DAN⁶, NAOSHI DOHMAE¹, HIROYUKI OSADA^2,7,*

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

* Corresponding Authors: MAKOTO KAWATANI. Email: ; HIROYUKI OSADA. Email:

(This article belongs to the Special Issue: Approach from Chemical Biology for Cancer Research)

Oncology Research 2023, 31(6), 833-844. https://doi.org/10.32604/or.2023.030241

Received 28 March 2023; Accepted 21 June 2023; Issue published 15 September 2023

Abstract

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.

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Supplementary Material

Supplementary Material File

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