Discovery of Novel Dual-Target Inhibitor of Bromodomain-Containing Protein 4/Casein Kinase 2 Inducing Apoptosis and Autophagy-Associated Cell Death for Triple-Negative Breast Cancer Therapy DOI
Jifa Zhang, Pan Tang, Ling Zou

et al.

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(24), P. 18025 - 18053

Published: Dec. 15, 2021

Bromodomain-containing protein 4 (BRD4) is an attractive epigenetic target in human cancers. Inhibiting the phosphorylation of BRD4 by casein kinase 2 (CK2) a potential strategy to overcome drug resistance cancer therapy. The present study describes synthesis multiple BRD4–CK2 dual inhibitors based on rational design, structure–activity relationship, and vitro vivo evaluations, 44e was identified possess potent balanced activities against (IC50 = 180 nM) CK2 230 nM). In experiments show that could inhibit proliferation induce apoptosis autophagy-associated cell death MDA-MB-231 MDA-MB-468 cells. two xenograft mouse models, displays anticancer activity without obvious toxicities. Taken together, we successfully synthesized first highly effective inhibitor, which expected be therapeutic for triple-negative breast (TNBC).

Language: Английский

Linker-Dependent Folding Rationalizes PROTAC Cell Permeability DOI Creative Commons
Vasanthanathan Poongavanam, Yoseph Atilaw, Stephan Siegel

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(19), P. 13029 - 13040

Published: Sept. 28, 2022

Proteolysis-targeting chimeras (PROTACs) must be cell permeable to reach their target proteins. This is challenging as the bivalent structure of PROTACs puts them in chemical space at, or beyond, outer limits oral druggable space. We used NMR spectroscopy and molecular dynamics (MD) simulations independently gain insights into origin differences permeability displayed by three flexible cereblon having closely related structures. Both methods revealed that propensity adopt folded conformations with a low solvent-accessible 3D polar surface area an apolar environment correlated high permeability. The nature flexibility linker were essential for populate stabilized intramolecular hydrogen bonds, π–π interactions, van der Waals interactions. conclude MD may prospective ranking design PROTACs.

Language: Английский

Citations

78
A bibliometric analysis of PROTAC from 2001 to 2021 DOI
Deping Li,

Dongmin Yu,

Yan Li

et al.

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 244, P. 114838 - 114838

Published: Oct. 14, 2022

Language: Английский

Citations

72
Polo-like Kinase 1 Inhibitors in Human Cancer Therapy: Development and Therapeutic Potential DOI
Jifa Zhang, Lele Zhang, Jiaxing Wang

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(15), P. 10133 - 10160

Published: July 25, 2022

Polo-like kinase 1 (PLK1) plays an important role in a variety of cellular functions, including the regulation mitosis, DNA replication, autophagy, and epithelial–mesenchymal transition (EMT). PLK1 overexpression is often associated with cell proliferation poor prognosis cancer patients, making it promising antitumor target. To date, at least 10 inhibitors (PLK1i) have been entered into clinical trials, among which typical domain (KD) inhibitor BI 6727 (volasertib) was granted "breakthrough therapy designation" by FDA 2013. Unfortunately, many other KD showed specificity, resulting dose-limiting toxicity, has greatly impeded their development. Researchers recently discovered PLK1i higher selectivity, stronger potency, better absorption, distribution, metabolism, elimination (ADME) characteristics. In this review, we emphasize structure–activity relationships (SARs) PLK1i, providing insights new drugs targeting for practice.

Language: Английский

Citations

70
Regulation of programmed cell death by Brd4 DOI Creative Commons
Jinfeng Hu, Dun Pan, Guo Li

et al.

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(12)

Published: Dec. 20, 2022

Abstract Epigenetic factor Brd4 has emerged as a key regulator of cancer cell proliferation. Targeted inhibition suppresses growth and induces apoptosis various cells. In addition to apoptosis, also been shown regulate several other forms programmed death (PCD), including autophagy, necroptosis, pyroptosis, ferroptosis, with different biological outcomes. PCD plays roles in development tissue homeostasis by eliminating unnecessary or detrimental Dysregulation is associated human diseases, cancer, neurodegenerative infectious diseases. this review, we discussed some recent findings on how actively regulates the therapeutic potentials targeting PCD-related A better understanding regulation would provide not only new insights into pathophysiological functions but avenues for therapy Brd4-regulated PCD.

Language: Английский

Citations

50
Bromodomain inhibitors and therapeutic applications DOI Creative Commons
G. Bharath Kumar, Ming‐Ming Zhou

Current Opinion in Chemical Biology, Journal Year: 2023, Volume and Issue: 75, P. 102323 - 102323

Published: May 17, 2023

Language: Английский

Citations

33
Epigenetic Targets and Their Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis DOI

Xiaohui Miao,

Pan Liu, Yangyang Liu

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117463 - 117463

Published: March 1, 2025

Language: Английский

Citations

2
FOXF2 expression triggered by endocrine therapy orchestrates therapeutic resistance through reorganization of chromatin architecture in breast cancer DOI
Rui Zhang,

Wen-Jing Jiang,

Shuai Zhao

et al.

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217463 - 217463

Published: Jan. 1, 2025

Language: Английский

Citations

1
BRD4 in physiology and pathology: ‘‘BET’’ on its partners DOI
Yin Liang,

Jieyi Tian,

Tao Wu

et al.

BioEssays, Journal Year: 2021, Volume and Issue: 43(12)

Published: Oct. 26, 2021

Bromodomain-containing 4 (BRD4), a member of Bromo and Extra-Terminal (BET) family, recognizes acetylated histones is importance in transcription, replication, DNA repair. It also binds non-histone proteins, RNA, contributing to development, tissue growth, various physiological processes. Additionally, BRD4 has been implicated driving diverse diseases, ranging from cancer, viral infection, inflammation neurological disorders. Inhibiting its functions with BET inhibitors (BETis) suppresses the progression several types creating an impetus for translating these chemicals clinic. The roles are largely dependent on interaction partners different contexts. In this review we discuss molecular mechanisms interacting physiology pathology. Current development BETis summarized. Further understanding will facilitate resolving liabilities present accelerate their clinical translation.

Language: Английский

Citations

53
Dual‐target inhibitors of bromodomain and extra‐terminal proteins in cancer: A review from medicinal chemistry perspectives DOI
Lu Feng, Guan Wang, Yi Chen

et al.

Medicinal Research Reviews, Journal Year: 2021, Volume and Issue: 42(2), P. 710 - 743

Published: Oct. 11, 2021

Abstract Bromodomain‐containing protein 4 (BRD4), as the most studied member of bromodomain and extra‐terminal (BET) family, is a chromatin reader interpreting epigenetic codes through binding to acetylated histones non‐histone proteins, thereby regulating diverse cellular processes including cell cycle, differentiation, proliferation. As promising drug target, BRD4 function closely related cancer, inflammation, cardiovascular disease, liver fibrosis. Currently, clinical resistance BET inhibitors has limited their applications but synergistic antitumor effects have been observed when used in combination with other tumor targeting additional components such PLK1, HDAC, CDK, PARP1. Therefore, designing dual‐target bromodomains rational strategy cancer treatment increase potency reduce resistance. This review summarizes structures biological functions discusses recent advances dual from medicinal chemistry perspective. We also discuss current design discovery strategies for inhibitors, providing insight into potential inhibitors.

Language: Английский

Citations

42
Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site DOI
Zhiqing Liu, Yi Li, Haiying Chen

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(3), P. 2388 - 2408

Published: Jan. 4, 2022

Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding this critical system and progress toward clinical development effective therapeutics. Here we report discovery a potent bromodomain 1 (BD1)-selective inhibitor ZL0590 (52) targeting unique, previously unreported binding site, while exhibiting significant anti-inflammatory activities in vitro vivo. X-ray crystal structural analysis complex with human BD1 associated mutagenesis study illustrate first-in-class nonacetylated lysine (KAc) site located at helix αB αC interface that contains important residues (e.g., Glu151) not commonly shared other spatially distinct from classic KAc recognition pocket. This new finding facilitates further elucidation biology underpinning specificity its protein–protein interaction partners.

Language: Английский

Citations

39