Last update 01 Nov 2024

BRD4 x SRC

Last update 01 Nov 2024

Basic Info

Related Targets

BRD4SRC

Drugs associated with BRD4 x SRC

HL403

Target

BRD4 x SRC

Mechanism

BRD4 inhibitors [+1]

Active Org.

Shenzhen University

Originator Org.

Shenzhen University

Active Indication

Triple Negative Breast Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with BRD4 x SRC

100 Translational Medicine associated with BRD4 x SRC

0 Patents (Medical) associated with BRD4 x SRC

Literatures (Medical) associated with BRD4 x SRC

01 Jan 2024·European Journal of Medicinal Chemistry

Design and synthesis of dual BRD4/Src inhibitors for treatment of triple-negative breast cancer

Article

Author: Sun, Fan ; Wang, Ying ; Zhang, Ming ; Chen, Lu ; Zhao, Man ; Li, Guofeng ; Xie, Yubao ; Xu, Shiyu ; Wang, Rui ; Hong, Liang ; Huang, Aima ; Li, Min

Triple-negative breast cancer (TNBC) is an extremely aggressive tumor with limited treatment options and effectiveness. Dual-target inhibitors capable of simultaneously suppressing invasion may represent a promising therapeutic approach for TNBC. In this work, we developed a series of dual BRD4/Src inhibitors by connecting JQ1 and dasatinib using various linkers and evaluated their efficacy against TNBC both in vitro and in vivo. Among these compounds, HL403 demonstrated IC₅₀ values of 133 nM for BRD4 inhibition and 4.5 nM for Src inhibition. Most importantly, HL403 not only exhibited potent anti-proliferative capabilities, but also effectively suppressed the invasion of MDA-MB-231 cells in vitro. Finally, the anti-tumor efficacy of HL403 was validated in a mouse MDA-MB-231 xenograft tumor model, achieving a tumor growth inhibition rate (TGI) of 70.7 %, which was superior to the combination of JQ1 and dasatinib (TGI = 54.0 %). Our research provides a promising and feasible new strategy for improving the treatment of TNBC.

03 Jun 2022·OncogeneQ1 · MEDICINE

Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer

Q1 · MEDICINE

Article

Author: Wei, Enwei ; Zeng, Lei ; Ji, Donglei ; Jia, Yanjie ; Shang, Guanglei ; Zhang, Qiang ; Wang, Chunyu

CUB domain-containing protein 1 (CDCP1), a transmembrane protein with tumor pro-metastatic activity, is highly expressed in late-stage and castrate-resistant prostate cancer (CRPC). However, the molecular mechanism driving CDCP1 overexpression in CRPC progress remains elusive. Here we report that transcription cofactors BRD4 and CBP/p300 co-regulate transcriptional expression of CDCP1 in CRPC tumorigenesis. In contrast to androgen receptor (AR) in CRPC, increased expression of BRD4 and CBP/p300 is strongly correlated with CDCP1 gene amplification. Combined knockdown or dual-inhibition of BRD4 and CBP/p300 down-regulated CDCP1 transcription and downstream PI3K/AKT and/or SRC/MAPK signaling pathways in CRPC cells much more so than single-protein perturbation. Our biochemical and structural analyses further showed that NEO2734, a dual-inhibitor targeting BRD4 and p300 bromodomains exhibits greater efficacy than single inhibitors for BRD4 or CBP/p300 in suppressing CDCP1 transcriptional expression and its downstream signaling pathways in CRPC cell proliferation and metastasis. Our study illustrates that targeting CDCP1 through dual-inhibition of BRD4 and CBP/p300 represents a synergistic therapeutic strategy for new treatment of CRPC.

01 Dec 2020·Cellular OncologyQ2 · MEDICINE

BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways

Q2 · MEDICINE

ArticleOA

Author: Chen, Li ; Liu, Zeyi ; Xu, Bingwei ; Wei, Xiaowei ; Zhang, Yang ; Shi, Junfeng ; Xu, Li ; Craven, Rolf ; Yang, Helen ; Pan, Yueyin ; Lu, Xinlan ; Liu, Chunming ; Thibault, Olivier ; Hamad, Nevean ; Qian, Hai ; Wei, Dongping ; Zheng, Xucai ; Wu, Yadi ; Yang, Xiuwei H ; Zhou, Binhua P ; Huang, Jian-An ; Napier, Dana ; Wang, Chi ; Li, Jieming ; He, Shuixiang

AbstractPurposeStemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a transcriptional and epigenetic mediator, for TNBC.MethodsTwo independent patient cohorts were subjected to bioinformatic and IHC examination for clinical association of candidate cancer drivers. The efficacy and biological bases for co-targeting these drivers were interrogated using cancer cell lines, a protein kinase array, chemical inhibitors, RNAi/CRISPR/Cas9 approaches, and a 4 T1-Balb/c xenograft model.ResultsWe found that amplification of the chromosome 8q24 region occurred in nearly 20% of TNBC tumors, and that it coincided with co-upregulation or amplification of c-Myc and FAK, a key effector of integrin-dependent signaling. This co-upregulation at the mRNA or protein level correlated with a poor patient survival (p < 0.0109 or p < 0.0402, respectively). Furthermore, we found that 14 TNBC cell lines exhibited high vulnerabilities to the combination of JQ1 and VS-6063, potent pharmacological antagonists of the BRD4/c-Myc and integrin/FAK-dependent pathways, respectively. We also observed a cooperative inhibitory effect of JQ1 and VS-6063 on tumor growth and infiltration of Ly6G+ myeloid-derived suppressor cells in vivo. Finally, we found that JQ1 and VS-6063 cooperatively induced apoptotic cell death by altering XIAP, Bcl2/Bcl-xl and Bim levels, impairing c-Src/p130Cas-, PI3K/Akt- and RelA-associated signaling, and were linked to EMT-inducing transcription factor Snail- and Slug-dependent regulation.ConclusionBased on our results, we conclude that the BRD4/c-Myc- and integrin/FAK-dependent pathways act in concert to promote breast cancer cell survival and poor clinical outcomes. As such, they represent promising targets for a synthetic lethal-type of therapy against TNBC.

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