Novel Dual BET and PLK1 Inhibitor WNY0824 Exerts Potent Antitumor Effects in CRPC by Inhibiting Transcription Factor Function and Inducing Mitotic Abnormality

Abstract

Castration-resistant prostate cancer (CRPC) is a lethal disease with few treatment alternatives once patients become resistant to second-generation anti-androgens. In CRPC, BET proteins are key regulators of AR-and MYC-mediated transcription, while the PLK1 inhibitor potentially downregulates AR and MYC besides influencing the cell cycle. Therefore, synchronous inhibition of BET and PLK1 would be a promising approach for CRPC therapy. This study developed a dual BET and PLK1 inhibitor WNY0824 with nanomolar and equipotent inhibition of BRD4 and PLK1. In vitro, WNY0824 exhibited excellent anti-proliferation activity on AR-positive CRPC cells and induced apoptosis. These activities are attributable to its disruption of the AR-transcriptional program and the inhibition of the ETS pathway. Furthermore, WNY0824 downregulated MYC and induced mitotic abnormality. In vivo, oral WNY0824 administration suppressed tumor growth in the CRPC xenograft model of enzalutamide resistance. These findings suggest that WNY0824 is a selective dual BET and PLK1 inhibitor with potent anti-CRPC oncogenic activity and provides insights into the development of other novel dual BET-and PLK1-inhibiting drugs.Research.

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

“…Using the MM/PBSA approach, we estimated the total binding free energies involved in the interaction of WNY0824 with the two macromolecules and our results showed that WNY0824 binds favorably with BRD4‐BD1 and PLK1 with total binding energy values of −42.50 kcal/mol and −51.64 kcal/mol, respectively ( Table 1). Though the observed difference in the estimated Δ G values could translate to dissimilar modes of binding of WNY0824 at the different protein binding sites, the higher value attributed to binding at PLK1 binding site signify considerably higher potency of WNY0824 at the binding site compared to BRD4‐BD1 which is in accordance with experimentally obtained values of IC 50 and Ki values estimated by Xu et al, 2020 [36] . The disparity could also be attributed to the variation in binding site amino acid sequences as well as binding site amino acid conservation.…”

“…Also, in a separate investigation probing the dual inhibitory capability of WNY0824 against BRD4 and PLK1, Xu et al . 2020 revealed the nanomolar inhibitory activity of WNY0824 to be 109.30 nM in the BRD4 protein and 22.30 nM in the PLK1 protein [36] . While they posited that these IC 50 values are equipotent in both proteins especially since they recorded excellent anti‐proliferation activity of the compound, we believe the apparent and age‐long shortcomings of using molecular docking studies [60] in isolation necessitates further investigations such as molecular dynamic simulations.…”

“…Though the observed difference in the estimated ΔG values could translate to dissimilar modes of binding of WNY0824 at the different protein binding sites, the higher value attributed to binding at PLK1 binding site signify considerably higher potency of WNY0824 at the binding site compared to BRD4-BD1 which is in accordance with experimentally obtained values of IC 50 and Ki values estimated by Xu et al, 2020. [36] The disparity could also be attributed to the variation in binding site amino acid sequences as well as binding site amino acid conservation. Also, relatively higher van der Waals interactions were shown to be involved in the binding of WNY0824 at PLK1 binding site relative to BRD4-BD1 binding site.…”

“…One of the newly synthesized compounds with proven dual potency on both BRD4 and PLK1 was WNY0824. [36] It was reported that WNY0824 possesses nanomolar range inhibition with excellent anti-proliferative activity on AR-positive CRPC cells in vitro. To support the experimental evidence reported earlier, we have employed computational methodologies to provide insight at the atomistic level to the possible inhibitory mechanism of WNY0824 against BRD4 and PLK1.…”

“…New compounds with dual inhibitory potential have been the hallmark of research recently. One of the newly synthesized compounds with proven dual potency on both BRD4 and PLK1 was WNY0824 [36] . It was reported that WNY0824 possesses nanomolar range inhibition with excellent anti‐proliferative activity on AR‐positive CRPC cells in vitro .…”