We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NH-pyrazole group into the 9H-pyrimido[4,5-b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with K_i values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in both triple-negative breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development.

中文翻译：

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CF53作为强效和口服生物可用的溴结构域和末端（BET）溴结构域抑制剂的基于结构的发现

我们报告基于结构的发现CF53（28）作为bromodomain和额外的终端（BET）蛋白质的高效和口服活性抑制剂。通过将NH-吡唑基团掺入9H-嘧啶并[4,5- b ]吲哚核中，我们鉴定了一系列与K _i结合BRD4 BD1蛋白的化合物值小于1 nM，并且在白血病和乳腺癌细胞的细胞生长抑制中实现了低纳摩尔浓度的效价。最有前途的化合物CF53具有出色的口服药代动力学特性，并且在小鼠三阴性乳腺癌和急性白血病异种移植模型中均具有显着的抗肿瘤活性。CF53与BRD4 BD1蛋白的共晶体结构的确定为其对BET蛋白的高结合亲和力提供了结构基础。CF53对非BET含溴结构域的蛋白质具有很高的选择性。这些数据将CF53确立为一种有效的，选择性的和口服活性的BET抑制剂，因此有必要对先进的临床前开发进行进一步评估。