Background:
The selective targeting of CREB-cAMP-responsive element-binding
protein (CBP) has recently evolved as a vital therapeutic approach for curtailing its aberrant
upregulation associated with the development of prostate cancer. Inhibition of CBP has been
discovered to be an important therapeutic option in androgen receptor signalling pathway mediated
prostate cancer. Y08197, a novel selective inhibitor of CBP, has shown promising therapeutic
outcome in prostate carcinogenesis over non-selective analogues such as CPI-637.
Methods/Results:
Herein, we used molecular dynamics simulation to gain insights into the
mechanistic and selective targeting of Y08197 at the bromodomain active site. Molecular
Mechanics/ Poisson-Boltzmann Surface Area (MM/PBSA) analysis revealed a similar inhibitory
effect between Y08197 and CPI-637. Furthermore, in exploring the selective affinity of Y08197
towards CBP in combination with Bromodomain and PHD finger-containing protein 1(BRPF1),
our findings highlighted Asp1116 as the ‘culprit’ residue responsible for this selective targeting.
Upon binding, Asp1116 assumed a conformation that altered the architecture of the bromodomain
active site, thereby orienting the helices around the active site in a more compacted position. In
addition to some specific structural perturbations mediated by Asp1116 on the dynamics of CBP,
our study revealed that the strong hydrogen bond interaction (N-H...O) elicited in CBP-Y08197
sequestered Y08197 tightly into the CBP bromodomain active site.
Conclusion:
Conclusively, the inhibition and selective pattern of Y08197 can be replicated in
future structure-based CBP inhibitors and other bromodomain implicated in carcinogenesis.
hZIP1 zinc transporter down-regulation in prostate cancer involves the overexpression of ras responsive element binding protein-1 (RREB-1)