Structural insights revealed by the cocrystal structure of CCS1477 in complex with CBP bromodomain
Hongrui Xu 1, Guolong Luo 2, Tianbang Wu 3, Jiankang Hu 2, Chao Wang 2, Xishan Wu 4, Yan Zhang 5, Yong Xu 6, Qiuping Xiang 7
Inhibition from the bromodomain from the CREB (cyclic-AMP response element-binding protein) binding protein (CBP) is an especially promising new therapeutic method for cancer. Benzimidazole derivatives CCS1477 and it is analogues (8 and 9) are highly potent and selective CBP bromodomain inhibitors, with Kd values of 26.4, 37., and 34.3 nM in ITC assay, correspondingly. Of these compounds, CCS1477 is undergoing phase Ib/IIa numerous studies to treat various cancers. Thus, we determined the co-very structures of CCS1477 and it is analogues in complex with CBP bromodomain and revealed the detailed binding modes. In addition, overlapping along with other reported co-very structures permitted us to recognize that interaction with Arg1173, LPF shelf, and ZA funnel was crucial for keeping strong biological activity and selectivity. With each other, this research provided a structural grounds for CBP bromodomain inhibitors design.Inobrodib