CBP bromodomain could recognize acetylated lysine and function as transcription coactivator to regulate transcription and downstream gene expression. Furthermore, CBP has been shown to be related to many human malignancies including acute myeloid leukemia. Herein, we identified DC-CPin734 as a potent CBP bromodomain inhibitor with a TR-FRET IC₅₀ value of 19.5 ± 1.1 nM and over 400-fold of selectivity against BRD4 bromodomains through structure based rational drug design guided iterative chemical modification endeavoring to discover optimal tail-substituted tetrahydroquinolin derivatives. Moreover, DC-CPin734 showed potent inhibitory activity to AML cell line MV4-11 with an IC₅₀ value of 0.55 ± 0.04 μM, and its cellular on-target effects were further evidenced by c-Myc downregulation results. In summary, DC-CPin734 showing good potency, selectivity and anti AML activity could serve as a potent and selective in vitro and in vivo probe of CBP bromodomain and a promising lead compound for future drug development.

CBP bromodomain可以识别乙酰化的赖氨酸，并作为转录共激活因子来调节转录和下游基因表达。此外，CBP已显示与许多人类恶性肿瘤有关，包括急性髓细胞性白血病。在本文中，我们确定DC-CPin734是有效的CBP溴结构域抑制剂，其TR-FRET IC ₅₀值为19.5±1.1 nM，并且通过基于结构的合理药物设计指导迭代化学修饰，从而努力发现最佳的BRD4溴结构域选择性超过400倍尾取代的四氢喹啉衍生物。此外，DC-CPin734对IC _50的AML细胞MV4-11表现出有效的抑制活性c-Myc下调的结果进一步证明了其值为0.55±0.04μM，并进一步证明了其对细胞的靶向作用。总之，显示出良好的效能，选择性和抗AML活性的DC-CPin734可作为CBP溴结构域的有效和选择性体外和体内探针，并有望成为未来药物开发的先导化合物。