Mechanistic Insights into the Selective Dual BET and PLK1 Inhibitory Activity of a Novel Benzamide Compound in Castration-Resistant Prostrate Cancer.

Though multifactorial, BET and PLK1 proteins have been found to be key players in the oncogenic process leading to castration-resistant prostate cancer through regulation of AR and MYC-mediated transcription. Hence, dual inhibition of these proteins appears to be an auspicious approach for CRPC therapy. WNY0824 has been reported to exhibit nanomolar range inhibition as well as significant anti-proliferative activity on AR-positive CRPC cells in vitro. However, structural, and mechanistic events associated with its dual inhibitory and anti-proliferative mechanisms remain unclear. Utilizing integrative computer-assisted atomistic techniques, analyses revealed that the dual-inhibitory activity of WNY0824 against BRD4 and PLK1 proteins is mediated by conserved residues present in the binding cavities of both proteins which are shown to elicit various strong intermolecular interactions and thus favour binding affinity. Also, binding orientation of the ligand at the protein binding cavities allowed for important hydrophobic interactions which resulted in high binding free energy of -42.50 kcal/mol and -51.64 kcal/mol towards BRD4 and PLK1, respectively. While van der Waals interactions are very important to ligand binding in BRD4-WNY complex, electrostatic interactions are pertinent to PLK1-WNY complex. Intriguingly, WNY0824 triggered conformational alterations in both proteins through increased structural instability, decreased structural compactness and mitigation in exposure of residues to solvent surface area. Consequently, critical interactions peculiar to the oncogenic activities of BRD4 and PLK1 were inhibited, a phenomenon that results in an antagonism of CRPC progression. The mechanistic insights presented in this report would further assist in the structure-based design of improved inhibitors useful in CRPC therapy.