Histone deacetylase inhibitors merged with protein tyrosine kinase inhibitors

Zhou, Nan; Xu, Wenfang; Zhang, Yingjie

doi:10.5582/ddt.2015.01001

Cited by 11 publications

(6 citation statements)

References 40 publications

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“…Some of FDA‐approved protein tyrosine kinase (PTK) inhibitors with their targets and year of approval…”

Section: Design Of Dual Protein Tyrosine Kinase (Ptk) Hdac Inhibitorsmentioning

confidence: 99%

“…Unfortunately, the elevated resistance rates have restricted their use, and after the many troubles resulting from their combinations with other anticancer drugs, medicinal chemistry research groups adopted the idea of hybridization, especially with HDAC inhibitors due to the flexible structure activity relationship (SAR) of HDAC inhibitors and the potential synergism between HDAC and EGFR inhibitors …”

Section: Design Of Dual Protein Tyrosine Kinase (Ptk) Hdac Inhibitorsmentioning

confidence: 99%

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Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

Hesham

Lasheen

Abouzid

2018

Medicinal Research Reviews

120

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Recently, molecular hybridization paradigm became an interesting and smart way to defeat the multifaceted cancer disease by a single molecular entity that acts via several mechanisms just like a magic bullet. Also, HDAC is an important epigenetic target in drug discovery, and the HDAC inhibitors showed successful pattern as cytotoxic agents. Because of their flexible structure activity relationship, it was easy to link them to other anticancer scaffolds. So, many dual action HDAC inhibitors have been developed and most of these hybrids have higher potency than the constituting parents in fighting of the cancer cells. This review describes potential applications of chimeric HDAC inhibitors, which simultaneously modulate not only HDAC but also multiple targets, in treatment of relapsing and drug-resistant cancers. We have nearly collected most of the reported dual action HDAC inhibitors yet to provide a comprehensive guide for the drug discovery process for developing more efficient anticancer agents.

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“…Some of FDA‐approved protein tyrosine kinase (PTK) inhibitors with their targets and year of approval…”

Section: Design Of Dual Protein Tyrosine Kinase (Ptk) Hdac Inhibitorsmentioning

confidence: 99%

Section: Design Of Dual Protein Tyrosine Kinase (Ptk) Hdac Inhibitorsmentioning

confidence: 99%

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

Hesham

Lasheen

Abouzid

2018

Medicinal Research Reviews

120

View full text Add to dashboard Cite

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“…Interestingly, new chimeric HDAC inhibitors merged with protein tyrosine kinase inhibitors [62] have been recently synthesized. These chimeric compounds retain both selective pharmacological activities, postulating a broader activity spectrum and less likelihood of drug resistance in cancer patients [63].…”

Section: Histone Modificationsmentioning

confidence: 99%

Epigenetics in Medullary Thyroid Cancer: From Pathogenesis to Targeted Therapy

Mantovani

Dicitore²,

Sciammarella³

et al. 2016

PRA

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“…Nevertheless, kinase inhibitors' as well as HDAC inhibitors effectiveness is often diminished and their use is restricted because of acquired drug resistance and consequently poor response rates [26,27]. To overcome this problem, medicinal chemistry investigators adopted the hybridization idea, principally with HDAC inhibitors due to either the ease of their structure modification or the likely synergism between HDAC and tyrosine kinase inhibitors which has been widely documented [28][29][30][31][32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors

2021

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Recently, combining histone deacetylase (HDAC) inhibitors with chemotherapeutic drugs or agents, in particular epidermal growth factor receptor (EGFR) inhibitors, is considered to be one of the most encouraging strategy to enhance the efficacy of the antineoplastic agents and decrease or avoid drug resistance. Therefore, in this work, based on introducing 3,4,5-trimethoxy phenyl group as a part of the CAP moiety, in addition to incorporating 4–6 aliphatic carbons linker and using COOH or hydroxamic acid as ZBG, 12 novel EGFR/HDAC hybrid inhibitors 2a–c, 3a–c, 4a–c and 5a–c were designed, constructed, and evaluated for their anticancer activities against 4 cancer cell lines (HepG2, MCF-7, HCT116 and A549). Among all, hybrids with hydroxamic acid 4a–c and 5a, exhibited the highest inhibition against all cancer cell lines with IC50 ranging from 0.536 to 4.892 μM compared to Vorinostat (SAHA) with IC50 ranging from 2.43 to 3.63 μM and Gefitinib with IC50 ranging from 1.439 to 3.366 μM. Mechanistically, the most potent hybrids 4a–c and 5a were further tested for their EGFR and HDACs inhibitory activities. The findings disclosed that hybrid 4b displayed IC50 = 0.063 µM on the target EGFR enzyme which is slightly less potent than the standard Staurosporine (IC50 = 0.044 µM). Furthermore, hybrid 4b showed less HDAC inhibitory activity IC50 against HDAC1 (0.148), 2 (0.168), 4 (5.852), 6 (0.06) and 8 (2.257) than SAHA. In addition, the investigation of apoptotic action of the most potent hybrid 4b showed a significant increase in Bax level up to 3.75-folds, with down-regulation in Bcl2 to 0.42-fold, compared to the control. Furthermore, hybrid 4b displayed an increase in the levels of Caspases 3 and 8 by 5.1 and 3.15 folds, respectively. Additionally, the cell cycle analysis of hybrid 4b revealed that it showed programmed cell death and cell cycle arrest at G1/S phase. Moreover, all these outcomes together with the molecular docking study recommended the rationalized target hybrids 4a–c and 5a, particularly 4b, may be considered to be promising lead candidates for discovery of novel anticancer agents via dual inhibition of both EGFR/HDAC enzymes.

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Histone deacetylase inhibitors merged with protein tyrosine kinase inhibitors

Cited by 11 publications

References 40 publications

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

Epigenetics in Medullary Thyroid Cancer: From Pathogenesis to Targeted Therapy

Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors

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