BRD4 inhibitors(Bromodomain-containing protein 4 inhibitors), MYC inhibitors(Myc proto-oncogene protein inhibitors), PLK1 inhibitors(Polo like kinase 1 inhibitors)

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication-

Inactive Indication

Castration-Resistant Prostatic Cancer

Originator Organization

Sichuan University

Active Organization-

Inactive Organization

Sichuan University

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC31H43N9O2

InChIKeyQUMCIHKVKQYNPA-RUZDIDTESA-N

CAS Registry2412707-81-2

100 Clinical Results associated with WNY-0824

100 Translational Medicine associated with WNY-0824

100 Patents (Medical) associated with WNY-0824

Literatures (Medical) associated with WNY-0824

01 Jan 2022·European Journal of Medicinal ChemistryQ1 · MEDICINE

Identification of a selective BRD4 PROTAC with potent antiproliferative effects in AR-positive prostate cancer based on a dual BET/PLK1 inhibitor

Q1 · MEDICINE

Article

Author: Hu, Rong ; Wang, Ning-Yu ; Wang, Wan-Li ; Xu, Ying ; Yang, Ying-Yue ; Wang, Qi-Wei ; Zuo, Wei-Qiong ; Hu, Xia-Tong ; Feng, Qiang

BRD4-targeted proteolysis targeting chimera (PROTAC) have exhibited promising in vitro and in vivo anticancer activity in a number of cancer models. However, the clinical development of current reported BRD4-PROTACs have stagnated, largely due to the safety risks caused by their poor degradation selectivity. In this study, we designed and synthesized a series of PROTACs based on our recently reported dual BET/PLK1 inhibitor WNY0824, which led to the discovery of an isoform-selective and potent BRD4-PROTAC 12a (WWL0245). WWL0245 exhibited excellent selective cytotoxicity in the BETi sensitive cancer cell lines, including AR-positive prostate cancer cell lines. It could also efficiently induce ubiquitin-proteasomal degradation of BRD4 in AR-positive prostate cancer cell lines, with sub-nanomolar half-maximal degrading concentration (DC₅₀) and maximum degradation (D_max) > 99%. Moreover, WWL0245 induced cell cycle arrest at the G0/G1 phase and apoptosis in AR-positive prostate cancer by downregulation of the protein levels of AR, PSA and c-Myc as well as transcriptionally suppressed AR-regulated genes. WWL0245 was thus expected to be developed as a promising drug candidate for AR-positive prostate cancer and a valuable tool compound to study the biological function of BRD4.

01 Dec 2021·Chemistry & BiodiversityQ3 · CHEMISTRY

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

Q3 · CHEMISTRY

Article

Author: Omolabi, Kehinde F. ; Subair, Temitayo I. ; Soliman, Mahmoud E. S. ; Akawa, Oluwole B. ; Okunlola, Felix O.

AbstractThough 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.

01 Jun 2020·Molecular Cancer TherapeuticsQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Song, Xuejiao ; Gao, Tiantao ; Liu, Zhihao ; Wang, Qianqian ; Hu, Xi ; Zuo, Weiqiong ; Zeng, Jun ; Yu, Luoting ; Xiao, Kunjie ; Feng, Zhanzhan ; Wang, Ningyu ; Zhao, Lifeng ; Xu, Ying

AbstractCastration-resistant prostate cancer (CRPC) is a lethal disease with few treatment alternatives once patients become resistant to second-generation antiandrogens. 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 antiproliferation 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.

100 Deals associated with WNY-0824

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Castration-Resistant Prostatic Cancer	Preclinical	CN	Sichuan University	27 Mar 2020

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