Identification of a dihydroorotate dehydrogenase inhibitor that inhibits cancer cell growth by proteomic profiling
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
Oncology Research, Vol.31, No.6, pp. 833-844, 2023, DOI:10.32604/or.2023.030241
(This article belongs to this Special Issue:
Approach from Chemical Biology for Cancer Research)
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…
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