Identification of Dihydroorotate Dehydrogenase Inhibitors─Indoluidins─That Inhibit Cancer Cell Growth,ACS Chemical Biology

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Identification of Dihydroorotate Dehydrogenase Inhibitors─Indoluidins─That Inhibit Cancer Cell Growth
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-11-03 , 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}

Affiliation

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.

中文翻译：

鉴定抑制癌细胞生长的二氢乳清酸脱氢酶抑制剂─Indoluidins

二氢乳清酸脱氢酶 (DHODH) 催化嘧啶从头生物合成中的限速步骤，是一种有前途的癌症治疗靶点。本研究报告了吲哚鲁丁 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鲁丁 D 促进骨髓分化并抑制急性早幼粒细胞白血病 HL-60 细胞的增殖。Indoluidin D 还抑制了各种其他类型癌细胞的细胞生长。使用 JFCR39 进行的癌细胞敏感性分析和使用 ChemProteoBase 进行的蛋白质组学分析显示吲哚鲁丁 D 是一种 DHODH 抑制剂。Indoluidin D 在体外抑制人 DHODH 活性；DHODH 反应产物乳清酸挽救了吲哚鲁丁 D 诱导的细胞分化。我们合成了几种吲哚鲁丁 D 非对映异构体衍生物，并证明立体化学对其分子活性至关重要。indoluidin D 衍生物 indoluidin E 在小鼠肺癌异种移植模型中显示出与其母体化合物相似的活性并抑制肿瘤生长。因此，吲哚鲁丁 D 及其衍生物选择性地抑制 DHODH 并抑制癌细胞生长。

更新日期：2021-11-19

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