Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China.
Bioorg Med Chem. 2022 Jul 15;66:116784. doi: 10.1016/j.bmc.2022.116784. Epub 2022 May 1.
Adenovirus E1A-associated 300-k protein (p300) bromodomain, which regulates gene expression by recognizing acetylated lysine (KAc) of histone, is a promising target for the treatment of cancer. Herein, a series of potent p300 bromodomain inhibitors with novel CBP30-based scaffolds was discovered through bioisosterism and conformational restriction strategies. The most promising compound 1u showed more potent inhibitory activity (IC = 49 nM) against p300 bromodomain and anti-proliferative activity in various cancer cell lines compared to CBP30. Moreover, 1u suppressed the expression of c-Myc and induced G/G phase arrest and apoptosis in OPM-2 cells more potently than CBP30. This study provides new lead compounds for further research on the biological functions of p300.
腺病毒 E1A 相关的 300k 蛋白 (p300) 溴结构域通过识别组蛋白上乙酰化的赖氨酸 (KAc) 来调节基因表达，是治疗癌症的有前途的靶点。在此，通过生物等排和构象限制策略，发现了一系列具有新型 CBP30 骨架的强效 p300 溴结构域抑制剂。最有前途的化合物 1u 对 p300 溴结构域的抑制活性 (IC=49nM) 比 CBP30 更强，并在各种癌细胞系中显示出更强的抗增殖活性。此外，1u 比 CBP30 更有效地抑制 OPM-2 细胞中 c-Myc 的表达，并诱导 G/G 期阻滞和凋亡。这项研究为进一步研究 p300 的生物学功能提供了新的先导化合物。
