Reference - Detail
| RRC ID | 81768 |
|---|---|
| Author | Kawatani M, Aono H, Shimizu T, Ohkura S, Hiranuma S, Muroi M, Ogawa N, Ohishi T, Ohba SI, Kawada M, Yamazaki K, Dan S, Osada H. |
| Title | Identification of Dihydroorotate Dehydrogenase Inhibitors─Indoluidins─That Inhibit Cancer Cell Growth. |
| Journal | ACS Chem Biol |
| 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. |
| Volume | 16(11) |
| Pages | 2570-2580 |
| Published | 2021-11-19 |
| DOI | 10.1021/acschembio.1c00625 |
| PMID | 34730931 |
| MeSH | Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Cell Differentiation / drug effects Cell Line, Tumor Cell Proliferation / drug effects* Databases, Protein Dihydroorotate Dehydrogenase / antagonists & inhibitors* Enzyme Inhibitors / chemistry Enzyme Inhibitors / pharmacology* Humans Mice Proteomics Stereoisomerism Xenograft Model Antitumor Assays |
| Resource | |
| Human and Animal Cells | 1B2C6(RCB0795) 1C3D3(RCB0796) MIA Paca2(RCB0294) OS-RC-2(RCB0735) MG-63(RCB1890) Saos-2(RCB0428) K562(RCB0027) A431 Hep G2 A549 HeLa Jurkat HL-60 |