Identification of Dihydroorotate Dehydrogenase Inhibitors─Indoluidins─That Inhibit Cancer Cell Growth

  • ACS Chem Biol. 2021 Nov 19;16(11):2570-2580. doi: 10.1021/acschembio.1c00625.
Makoto Kawatani  1  2 ,  Harumi Aono  1 ,  Takeshi Shimizu  1 ,  Shouta Ohkura  1 ,  Sayoko Hiranuma  1 ,  Makoto Muroi  1  2 ,  Naoko Ogawa  1 ,  Tomokazu Ohishi  3 ,  Shun-Ichi Ohba  3 ,  Manabu Kawada  3 ,  Kanami Yamazaki  4 ,  Shingo Dan  4 ,  Hiroyuki Osada  1  2
Affiliations
  • 1. Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 2. Chemical Resource Development Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 3. Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu, Shizuoka 410-0301, Japan.
  • 4. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japan Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
PMID: 34730931 DOI: 10.1021/acschembio.1c00625
Abstract

Dihydroorotate Dehydrogenase (DHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis and is a promising Cancer treatment target. This study reports the identification of indoluidin D and its derivatives as inhibitors of DHODH. Cell-based phenotypic screening revealed that indoluidin D promoted myeloid differentiation and inhibited the proliferation of acute promyelocytic leukemia HL-60 cells. Indoluidin D also suppressed cell growth in various other types of Cancer cells. Cancer cell sensitivity profiling with JFCR39 and proteomic profiling with ChemProteoBase revealed that indoluidin D is a DHODH inhibitor. Indoluidin D inhibited human DHODH activity in vitro; the DHODH reaction product orotic acid rescued indoluidin D-induced cell differentiation. We synthesized several indoluidin D diastereomer derivatives and demonstrated that stereochemistry was vital to their molecular activity. The indoluidin D derivative indoluidin E showed similar activity to its parent compound and suppressed tumor growth in a murine Lung Cancer xenograft model. Hence, indoluidin D and its derivatives selectively inhibit DHODH and suppress Cancer cell growth.

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