@Article{or.2023.030241,
AUTHOR = {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},
TITLE = {Identification of a dihydroorotate dehydrogenase inhibitor that inhibits cancer cell growth by proteomic profiling},
JOURNAL = {Oncology Research},
VOLUME = {31},
YEAR = {2023},
NUMBER = {6},
PAGES = {833--844},
URL = {http://www.techscience.com/or/v31n6/54215},
ISSN = {1555-3906},
ABSTRACT = {Dihydroorotate dehydrogenase (DHODH) is a central enzyme of the <i>de novo</i> 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 <i>in vitro</i>, 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.},
DOI = {10.32604/or.2023.030241}
}