Last update 01 Nov 2024

BRD4 x JAK x HDACs

Last update 01 Nov 2024

Basic Info

Related Targets

BRD4JAKHDACs

Drugs associated with BRD4 x JAK x HDACs

25-ap

Target

BRD4 x HDACs x JAK

Mechanism

BRD4 inhibitors [+2]

Active Org.

Shandong University

Originator Org.

Shandong University

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with BRD4 x JAK x HDACs

100 Translational Medicine associated with BRD4 x JAK x HDACs

0 Patents (Medical) associated with BRD4 x JAK x HDACs

Literatures (Medical) associated with BRD4 x JAK x HDACs

27 Oct 2023·Current Medicinal Chemistry

A Combination of CPI-0610 and SAHA Induces Apoptosis through STAT3 and p38 Signalling Pathways in Diffuse Large B-cell Lymphoma Cells

Article

Author: Jiao, Jun ; Qin, Yuanyuan ; Liu, Mengdi ; Xu, Linyan ; Yan, Dongmei ; Sang, Wei ; Xu, Kailin ; Zhang, Meng

Background::Although immunotherapies have greatly improved diffuse large B-cell lymphoma (DLBCL) prognosis, a proportion of patients remain to be relapsed or refractory. Therefore, the identification of novel therapeutic targets and drugs is urgently required. Inhibition of the bromodomain and extra-terminal (BET) proteins has been a promising therapeutic strategy for various haematologic cancers. CPI-0610 is a potent and selective BET inhibitor. The effects of CPI-0610 in DLBCL cells have not been reported yet.Aims::The aim of this study was to assess the effects of CPI-0610 in DLBCL and its underlying mechanisms.Methods::DLBCL cells were treated with CPI-0610, followed by measuring cell viability, cell cycle, apoptosis, autophagy, and specific cell signaling pathways. Moreover, immunodeficient mice were engrafted with SUDHL2 cells and then treated with CPI-0610 for analysis of tumor burden. We also analyzed the synergistic effect of CPI-0610 with histone deacetylase inhibitor suberoylanilide hydroxamic acid.Results::The present study demonstrated that CPI-0610 displayed cell cytotoxicity by arresting the G1 cell cycle and inducing endogenous and exogenous apoptotic pathways. Additionally, CPI-0610 decreased BRD4 and c-Myc expressions and affected MAPK, JAK/STAT, and AKT signalling pathways in human DLBCL cells. An in vivo experiment exhibited that CPI-0610 decreased the primary tumour growth of the DLBCL xenograft model. Furthermore, the use of CPI-0610 in combination with suberoylanilide hydroxamic acid exhibited a specific synergistic effect in inducing apoptosis through the regulation of STAT3 and p38.Conclusion::Targeting BET may be an effective therapeutic strategy and potentiated by a combination with histone deacetylase inhibition in DLBCL.

26 Oct 2023·Journal of medicinal chemistryQ1 · MEDICINE

Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer.

Q1 · MEDICINE

Article

Author: Zhang, Jin'ge ; Liu, Fengling ; Meng, Hongwei ; Chai, Qipeng ; Geng, Yinping ; Zhang, Yu ; Li, Shunda ; Liu, Mengyang ; Zhang, Yingjie ; Zheng, Yichao ; Li, Jintao ; Zhao, Chunlong ; Li, Mengzhe

Multitarget HDAC inhibitors capable of simultaneously blocking the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based multitarget HDAC inhibitors were rationally designed, synthesized, and biologically evaluated, among which compound 25ap stood out as a potent HDAC/JAK/BRD4 triple inhibitor. Satisfyingly, compound 25ap led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3 signaling pathway, which was validated by hyper-acetylation of histone and α-tubulin, hypo-phosphorylation of STAT3, downregulation of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells. The multitarget effects of 25ap contributed to its robust antitumor response, including potent antiproliferative activity, remarkable apoptosis-inducing activity, and inhibition of colony formation. Notably, 25ap possessed an acceptable therapeutic window between normal and cancerous cells, desirable in vitro metabolic stability in mouse microsome, and sufficient in vivo exposure via intraperitoneal administration. Additionally, the in vivo antitumor potency of 25ap was demonstrated in an MDA-MB-231 xenograft model.

09 Apr 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Thieno[2,3-d]pyrimidine-Based Hydroxamic Acid Derivatives as Bromodomain-Containing Protein 4/Histone Deacetylase Dual Inhibitors Induce Autophagic Cell Death in Colorectal Carcinoma Cells

Q1 · MEDICINE

Article

Author: Jiang, Qinglin ; Wu, Fengbo ; He, Gu ; Zhang, Min ; Zhang, Nan ; Li, Xiang ; Jiang, Li ; Wang, Yujia ; Pan, Zhaoping ; Liu, Bo

Bromodomain-containing protein 4 (BRD4) and histone deacetylases (HDAC) are both attractive epigenetic targets in cancer and other chronic diseases. Based on the integrated fragment-based drug design, synthesis, and in vitro and in vivo evaluations, a series of novel thieno[2,3-d]pyrimidine-based hydroxamic acid derivatives are discovered as selective BRD4-HDAC dual inhibitors. Compound 17c is the most potent inhibitor for BRD4 and HDAC with IC₅₀ values at nanomolar levels, as well as the expression level of c-Myc, and increases the acetylation of histone H3. Moreover, 17c presents inhibitory effects on the proliferation of colorectal carcinoma (CRC) cells via inducing autophagic cell death. It also has a good pharmacokinetic profile in rats and oral bioavailability of 40.5%. In the HCT-116 xenograft in vivo models, 17c displays potent inhibitory efficiency on tumor growth by inducing autophagic cell death and suppressing IL6-JAK-STAT signaling pathways. Our results suggest that the BRD4-HDAC dual inhibition might be an attractive therapeutic strategy for CRC.

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