Last update 01 Nov 2024

c-Myc x BRD4 x PLK1

Last update 01 Nov 2024

Basic Info

Related Targets

c-MycBRD4PLK1

Drugs associated with c-Myc x BRD4 x PLK1

WNY-0824

Target

BRD4 x PLK1 x c-Myc

Mechanism

BRD4 inhibitors [+2]

Active Org.-

Originator Org.

Sichuan University

Active Indication-

Inactive Indication

Castration-Resistant Prostatic Cancer

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with c-Myc x BRD4 x PLK1

100 Translational Medicine associated with c-Myc x BRD4 x PLK1

0 Patents (Medical) associated with c-Myc x BRD4 x PLK1

Literatures (Medical) associated with c-Myc x BRD4 x PLK1

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 May 2021·Chemical Biology & Drug DesignQ4 · MEDICINE

Design, synthesis, and biological evaluation of novel 4,4‐difluoro‐1‐methyl‐N, 6‐diphenyl‐5, 6‐dihydro‐4H‐pyrimido [4, 5‐b] [1, 2, 4] triazolo [4, 3‐d] [1, 4] diazepin‐8‐amine derivatives as potential BRD4 inhibitors

Q4 · MEDICINE

Article

Author: Shi, Wei ; Zhang, Wenjie ; Tong, Zhenzhen ; Li, Jiuhui ; Huang, Wenlong ; Zhou, Daoguang ; Li, Jieming ; Feng, Ziying ; Wei, Jiaxin ; Qian, Hai ; Qiu, Qianqian

AbstractBromodomain‐containing protein 4 (BRD4) plays an extremely important physiological role in cancer, and the BRD4 inhibitors can effectively inhibit the proliferation of tumor cells. By taking BI‐2536 (PLK1 and BRD4 inhibitor) as the lead compound, sixteen novel BRD4 inhibitors with the 4,4‐difluoro‐1‐methyl‐N,6‐diphenyl‐5,6‐dihydro‐4H‐pyrimido[4,5‐b] [1,2,4] triazolo[4,3‐d] [1,4] diazepine‐8‐amine structure were designed and synthetized. Among the target compounds, compound 15h exhibited outstanding inhibition for BRD4‐BD1 (IC50 value of 0.42 μM) in the BRD4‐BD1 inhibitory activity assay. Additionally, cell growth inhibition assay demonstrated that compound 15h potently suppressed the proliferation of MV4‐11 cells (IC50 value of 0.51 μM). Besides, compound 15h induced apoptosis and G0/G1 cycle arrest in MV4‐11 leukemia cells effectively, and downregulated the expression of c‐Myc in a dose‐dependent manner. In summary, the optimal compound 15h is expected to become the clinical therapeutic drug for further research.

01 Jun 2020·Investigational New Drugs

A new BET inhibitor, 171, inhibits tumor growth through cell proliferation inhibition more than apoptosis induction

Article

Author: Tian, Chang-Qing ; Chen, Yue-Lei ; Hu, Jian-Ping ; Meng, Tao ; Miao, Ze-Hong ; Chen, Dan-Qi ; Damaneh, Mohammadali Soleimani ; Shen, Jing-Kang ; Huan, Xia-Juan ; Song, Shan-Shan ; Xiong, Bing ; Wang, Ying-Qing

The bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Compound 171 was found to maintain BET inhibition ability without PLK1 inhibition, and there was no selectivity among BET family members. The in vitro and in vivo results both indicated that the overall anti-tumor activity of compound 171 was improved compared with the (+)-JQ-1 or OTX-015 BET inhibitors. Furthermore, we found that compound 171 could regulate the expression of cell cycle-regulating proteins including c-Myc and p21 and induce cell cycle arrest in the G₀/G₁ phase. However, compound 171 only has a quite limited effect on apoptosis, in considering that apoptosis was only observed at doses greater than 50 μM. To determine the mechanisms underlying cell death, proliferation activity assay was conducted. The results showed that compound 171 induced clear anti-proliferative effects at doses that no obvious apoptosis was induced, which indicated that the cell cycle arresting effect contributed mostly to its anti-tumor activity. The result of this study revealed the anti-tumor mechanism of compound 171, and laid a foundation for the combination therapy in clinical practice, if compound 171 or its series compounds become drug candidates in the future.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis