We have designed and synthesized 9H-pyrimido[4,5-b]indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (31) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, 31 achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of 31 with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that 31 is a highly selective inhibitor of BET proteins. Our data show that 31 is a potent, selective, and orally active BET inhibitor.

中文翻译：

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基于结构的4-（6-甲氧基-2-甲基-4-（喹啉-4-基）-9H-嘧啶[4,5-b]吲哚-7-基）-3,5-二甲基异恶唑（CD161 ）作为有效的和口服生物可利用的BET溴结构域抑制剂。

我们设计并合成了含9H-嘧啶[4,5-b]吲哚的化合物，以获得有效的和口服可生物利用的BET抑制剂。通过将吲哚或喹啉部分掺入9H-嘧啶[4,5-b]吲哚核中，我们鉴定了一系列小分子，它们对BET蛋白显示出高结合亲和力，并且在抑制急性白血病细胞生长方面具有低纳摩尔浓度。细胞系。一种这样的化合物4-（6-甲氧基-2-甲基-4-（喹啉-4-基）-9H-嘧啶[4,5-b]吲哚-7-基）-3,5-二甲基异恶唑（31）在大鼠和小鼠中具有出色的微粒体稳定性和良好的口服药代动力学。口服31在小鼠的MV4; 11白血病和MDA-MB-231三阴性乳腺癌异种移植模型中实现了显着的抗肿瘤活性。用BRD4 BD2鉴定31的共晶体结构为其与BET蛋白的高结合亲和力提供了结构基础。测试其与其他含溴结构域蛋白的结合亲和力表明31是BET蛋白的高度选择性抑制剂。我们的数据表明31是一种有效的，选择性的和口服活性的BET抑制剂。