DHODH 抑制剂布雷奎纳的羧酸等排体筛选。
A carboxylic acid isostere screen of the DHODH inhibitor Brequinar.
机构信息
Discovery Chemistry, Janssen Pharmaceutical Research & Development, 1400 McKean Rd, Spring House, PA 19477, USA.
Oncology Discovery, Janssen Pharmaceutical Research & Development, 1400 McKean Rd, Spring House, PA 19477, USA.
出版信息
Bioorg Med Chem Lett. 2020 Nov 15;30(22):127589. doi: 10.1016/j.bmcl.2020.127589. Epub 2020 Sep 29.
Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.
二氢乳清酸脱氢酶 (DHODH) 的酶活性对细胞增殖和存活的许多关键方面都有影响。最近，DHODH 已被确定为急性髓系白血病分化治疗的靶点。在 AML 的临床前模型中，DHODH 抑制剂布雷奎纳 (BRQ) 表现出强大的抗白血病活性。本文描述了布雷奎纳的羧酸酯类似物研究，揭示了一种更有效的非羧酸衍生物，具有更好的细胞效力和良好的药代动力学特性。
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