Generation and Assessment of Fusions Between HDACi and TKi

Mahboobi, Siavosh; Pilsl, Bernadette; Sellmer, Andreas

doi:10.1007/978-1-4939-6527-4_31

Cited by 5 publications

(7 citation statements)

References 14 publications

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“…The design of RTKi/HDACi hybrids was proposed to overcome RTKi resistance, because combinations of HDACis and RTKis were shown to act synergistically [ 191 , 192 , 193 ]. Such a hybrid consists of a key fragment from the kinase inhibitor, tethered by the appropriate linker to a zinc binding group from HDACi, as shown in Figure 23 [ 194 ]. Many attempts were made to combine HDAC inhibitors and EGFR inhibitors in a single molecular entity [ 55 , 195 , 196 , 197 ].…”

Section: Hybrid Drugs As An Answer To the Anticancer Drug Resistance Problem?mentioning

confidence: 99%

Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

2021

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Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.

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Section: Hybrid Drugs As An Answer To the Anticancer Drug Resistance Problem?mentioning

confidence: 99%

Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

2021

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“…HDACis were shown to synergize with RTK inhibitors by suppressing proliferation and inducing apoptosis in tumor cells, making tumor cells more susceptible to RTK inhibitor treatment and even overcoming RTK inhibitor resistance. − Dual-acting hybrids that inhibit both HDAC and RTK have been widely reported. − The structural features of such hybrids consist of a key fragment from the kinase inhibitors and a ZBG group from the HDACis with an appropriate linker as shown in Figure . The resulting kinase/HDAC hybrid inhibitors can simultaneously inhibit both HDACs and kinases …”

Section: Kinase/hdac Hybrid Inhibitorsmentioning

confidence: 99%

“…The resulting kinase/HDAC hybrid inhibitors can simultaneously inhibit both HDACs and kinases. 38 A. Erlotinib-Based Hybrid HDACis. Cai et al designed and synthesized a series of compounds by integrating the hydroxamic acid group of an HDACi into the known epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) inhibitor erlotinib (6 in Figure 4).…”

Section: ■ Hybrid Hdacismentioning

confidence: 99%

Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy

et al. 2018

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Histone deacetylases (HDACs), encompassing at least 18 members, are promising targets for anticancer drug discovery and development. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It has been well validated that an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in preventing resistance to treatment and in potentiating synergistic effects. A prime example of a bifunctional agent is the hybrid HDAC inhibitor. In this perspective, the authors review the majority of reported kinase/HDAC hybrid inhibitors.

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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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Generation and Assessment of Fusions Between HDACi and TKi

Cited by 5 publications

References 14 publications

Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer 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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