Identification of Dihydroorotate Dehydrogenase Inhibitors-Indoluidins-That Inhibit Cancer Cell Growth
Identification of Dihydroorotate Dehydrogenase Inhibitors-Indoluidins-That Inhibit Cancer Cell Growth
复制标题
DOI：
10.1021/acschembio.1c00625
复制
发表时间：
2021-11-19
影响因子：
4
通讯作者：
Osada, Hiroyuki
中科院分区：
文献类型：
--
作者：
Kawatani, Makoto;Aono, Harumi;Osada, Hiroyuki
二氢羟酸脱氢酶（DHODH）催化了新的嘧啶生物合成的限速步骤，是一个很有前途的癌症治疗靶点。本研究报道了吲哚吲啶D及其衍生物作为DHODH抑制剂的鉴定。基于细胞的表型筛选显示吲哚醌D促进髓细胞分化，抑制急性早幼粒细胞白血病HL-60细胞增殖。吲哚吲啶D还能抑制其他类型癌细胞的生长。JFCR39的癌细胞敏感性分析和ChemProteoBase的蛋白质组学分析显示吲哚醌D是一种DHODH抑制剂。吲哚吲啶D体外抑制人DHODH活性；DHODH反应产物乳香酸挽救了吲哚醌d诱导的细胞分化。我们合成了几种吲哚吲啶D非对映体衍生物，并证明了立体化学对它们的分子活性至关重要。吲哚吲啶D衍生物吲哚吲啶E在小鼠肺癌异种移植模型中表现出与其母体化合物相似的活性，并抑制肿瘤生长。因此，吲哚醌D及其衍生物选择性地抑制DHODH，抑制癌细胞生长。
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.