Comprehensive review for anticancer hybridized multitargeting HDAC inhibitors

Bass, Amr K.A.; El‐Zoghbi, Mona S.; Nageeb, El-Shimaa M.; Mohamed, Mamdouh F. A.; Badr, Mohamed; Abuo‐Rahma, Gamal El‐Din A.

doi:10.1016/j.ejmech.2020.112904

Cited by 66 publications

(48 citation statements)

References 297 publications

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“…It must be underlined that the introduction of the pharmacophore for a second non-HDAC target would be impossible without a high degree of structural tolerance of the surface-binding cap, which enables the designing of multi-targeted molecules without compromising HDAC binding [ 50 ]. The number of multi-target HDACi hybrids reported in the literature is overwhelming [ 189 , 190 ]. The examples described below show an undeniable and significant role of these hybrids in overcoming anticancer drug resistance.…”

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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“…We started our project with reference to the well-established caplinker-metal binding group pharmacophore model for HDAC inhibitors. This model represented by a capping group is able to interact with the rim of the catalytic tunnel of the enzyme, opposite to a zinc-binding group (ZBG) at the bottom of the catalytic cavity, and a carbon linker connecting the two parts (27). To date, numerous studies have established that hydroxamic acid is a powerful Zn-chelating group; three Food and Drug Administration (FDA)-approved HDAC inhibitors (vorinostat, panobinostat, and belinostat; Figure 1A) also contain this ZBG (28).…”

Section: Design and Synthesis Of Curcumin-based Hdac Inhibitormentioning

confidence: 99%

A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma

2021

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Glioblastoma (GBM) is one of the most common primary and deadliest malignant brain tumor with chemoresistance and poor prognosis. There is a lack of effective chemotherapeutic drug for the treatment of GBM. In this work, we reported the preparation of a histone deacetylase (HDAC) inhibitor, DMC-HA, from the structural modification of natural product curcumin. DMC-HAs were tested in an HDAC inhibition assay and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cytotoxicity. It showed potent inhibition of HDAC1–2 and HDAC6 with IC50 values in the submicromolar concentration range. DMC-HA significantly inhibited the proliferation of human glioblastoma U87 cells and mediated apoptosis of U87 cells in a dose- and time-dependent manner. In addition, DMC-HA elevated the acetylation level of histone H3 in U87 cells. Pharmacokinetic studies showed that DMC-HA possessed acceptable pharmacokinetic profiles, accompanied with certain brain permeability. Lastly, we showed that DMC-HA suppressed the growth of tumor in U87 tumor xenograft model in vivo with no obvious toxicity. These results demonstrate that DMC-HA has the potential to be developed as a chemotherapeutic drug for GBM patients.

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“…Romidepsin is a naturally occurring compound that was first isolated in 1994 from the Gram negative bacterium Chromobacterium violaceum. The compound was evaluated as a novel antitumor antibiotic in 1994 and received FDA approval in 2011 for the treatment of peripheral T-cell lymphomas (PTCLs) (Barbarotta & Hurley, 2015;Shigematsu, Ueda, Takase & Tanaka, 1994;Ueda et al, 1994). Romidepsin is a prodrug that becomes active as a result of the reduction of the intramolecular disulfide bond.…”

Section: Romidepsin (Depsipeptide or Fk228)mentioning

confidence: 99%

“…Hybrid molecules of HDACIs have been designed with many drug groups such as topoisomerase, protein kinase, proteasome, phosphodiesterase type 5 (PDE5) and bromodomain containing 4 (BRD4) inhibitors. Of these, CUDC-101 (a molecule mentioned earlier) and fimepinostat (CUDC-907) are hybrid molecules in various clinical trial phases for the treatment of different types of cancer (Bass et al, 2021;Vaidya et al, 2021). Fimepinostat (CUDC-907), a dual inhibitor of HDAC and PI3K enzymes, has been shown to have more tumor growth inhibiting and pro-apoptotic activity in various cancer lines than single targeted agents that inhibit these enzymes (Younes et al, 2016).…”

Section: Future Directionsmentioning

confidence: 99%

Histone deacetylase inhibitors providing an epigenetic treatment in cancer

Karalı¹

2021

ijp

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Cancer is among the leading causes of death worldwide and is therefore one of the diseases in which there have been major medical advances and which is the focus of researchers. Drugs used in cancer treatment affect rapidly proliferating normal cells as well as cancer cells. In recent years, targeted therapy has been provided by identifying specific pathways in cancer cells. Epigenetic mechanisms are among the targeted therapies in cancer treatment. Epigenetic regulators ensure the continuity of the normal process by inducing epigenetic changes through epigenetic mechanisms such as DNA methylation, histone post-translational modifications, and non-coding RNA regulation. Histone deacetylases (HDACs), which are involved in transcription-independent events such as DNA repair and mitosis, are enzymes that remove acetyl groups attached to the lysine residue in the amino terminal tails of histones. Histone deacetylase inhibitors (HDACIs) that provide epigenetic treatment of cancer, which play a key role in the balance between acetylation and deacetylation of histone, have been extensively studied by researchers. Today, there are four HDACIs on the market approved by the FDA (Food and Drug Administration) and combinations of these drugs with agents that show anticancer activity by different mechanisms are being studied. Promising results have been obtained from these combinations, and further studies are ongoing on hybrid derivatives of certain HDACIs in various stages.

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Comprehensive review for anticancer hybridized multitargeting HDAC inhibitors

Cited by 66 publications

References 297 publications

Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma

Histone deacetylase inhibitors providing an epigenetic treatment in cancer

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