Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents

Cheng, Gaoliang; Wang, Zhi; Yang, Jinyu; Bao, Yu; Xu, Qihao; Zhao, Liang; Liú, Dan

doi:10.1016/j.bioorg.2018.12.011

Cited by 45 publications

(20 citation statements)

References 26 publications

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“…92 Compound 22 shows the inhibition of BRD4 at a rate of 88% at 10 μM and strong HDAC3 inhibition with an IC 50 value of 5 nM. 93 Compound 23, another dual BRD4/HDAC inhibitor, induces autophagic cell death in colorectal cancer (CRC) cells at nanomolar levels. 90 Compound 24 induces HL-60 AML cell death with c-MYC-inhibitory activity and suppresses cell growth in BET inhibitor-resistant cells.…”

Section: Development Of Next-generation Inhibitorsmentioning

confidence: 99%

Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

et al. 2021

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Bromodomain and extraterminal (BET) proteins bind acetylated lysine residues in histones and nonhistone proteins via tandem bromodomains and regulate chromatin dynamics, cellular processes, and disease procession. Thus targeting BET proteins is a promising strategy for treating various diseases, especially malignant tumors and chronic inflammation. Many pan-BET small-molecule inhibitors have been described, and some of them are in clinical evaluation. Nevertheless, the limited clinical efficacy of the current BET inhibitors is also evident and has inspired the development of new technologies to improve their clinical outcomes and minimize unwanted side effects. In this Review, we summarize the latest protein characteristics and biological functions of BRD4 as an example of BET proteins, analyze the clinical development status and preclinical resistance mechanisms, and discuss recent advances in BRD4-selective inhibitors, dual-target BET inhibitors, proteolysis targeting chimera degraders, and protein–protein interaction inhibitors.

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Section: Development Of Next-generation Inhibitorsmentioning

confidence: 99%

Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

et al. 2021

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“…Mass spectrometry analyses were performed with a Finnigan MAT710C (Thermo Separation Products, San Jose, CA, USA) for the ESIMS spectra and with a LTQ (linear ion trap) Orbitrap XL hybrid mass spectrometer (Thermo Fisher Scientific, Bremen, Germany) for the HRMS-ESI (high resolution mass spectrometry) spectra. For the HRMS analyses the signal for the isotopes with the highest prevalence was given and calculated ( 35 Cl, 79 Br). A mixture of the appropriate 4-substituted-3-formylbenzoate 8a-b (1.2 mmol) and 6-amino-1,3dimethylquinolin-2-(1H)-one (5; 1 mmol) was dissolved in toluene, and the reaction mixture was refluxed for 2 h using a dean stark apparatus.…”

Section: Generalmentioning

confidence: 99%

“…Bromodomains received also some interest in this regard, as some dual bromodomain/kinase inhibitors were investigated [71][72][73][74]. Of particular relevance to the current work are the attempts to design dual HDAC/BRD epigenetic inhibitors [75][76][77][78][79]. In all of the reported studies, the rationale was to change the cap group of HDACi, mostly SAHA, to a reported BRD4 inhibiting pharmacophore.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Ghazy

Zeyen

Herp

et al. 2020

European Journal of Medicinal Chemistry

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Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.

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“…The binding mode of P‐0014 (a BET inhibitor, 55 ) and BRD4 indicates that the ZA channel is not fully occupied. Cheng et al 150 speculated that the HDACi linker may be more beneficial to the ZA channel. P‐0014 is structurally similar to compound 56 with an indole skeleton present in an HDAC inhibitor, thus allowing the use of pharmacophore fusion to design and synthesize BET/HDAC inhibitors (Figure 13B).…”

Section: Dual‐target Inhibitors Of Bet Brds and Other Cancer‐related ...mentioning

confidence: 99%

Dual‐target inhibitors of bromodomain and extra‐terminal proteins in cancer: A review from medicinal chemistry perspectives

Feng

Wang

Chen

et al. 2021

Medicinal Research Reviews

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

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Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents

Cited by 45 publications

References 26 publications

Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Dual‐target inhibitors of bromodomain and extra‐terminal proteins in cancer: A review from medicinal chemistry perspectives

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