Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Bioorg Med Chem Lett. 2020 Nov 15;30(22):127480. doi: 10.1016/j.bmcl.2020.127480. Epub 2020 Aug 31.
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 IC 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 IC 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 溴结构域可以识别乙酰化的赖氨酸，并作为转录共激活因子发挥作用，调节转录和下游基因表达。此外，CBP 已被证明与许多人类恶性肿瘤有关，包括急性髓系白血病。在此，我们通过基于结构的合理药物设计，确定了 DC-CPin734 是一种有效的 CBP 溴结构域抑制剂，其通过反复进行化学修饰以发现最佳的取代四氢喹啉衍生物的努力，对 CBP 溴结构域的 TR-FRET IC 值为 19.5±1.1 nM，选择性超过 400 倍。此外，DC-CPin734 对 AML 细胞系 MV4-11 具有很强的抑制活性，IC 值为 0.55±0.04 μM，其细胞内靶标作用进一步通过 c-Myc 下调结果得到证实。总之，DC-CPin734 具有良好的活性、选择性和抗 AML 活性，可作为 CBP 溴结构域的有效、选择性的体外和体内探针，以及未来药物开发的有前途的先导化合物。
