Design, synthesis, and biological evalution of bifunctional inhibitors against Hsp90-HDAC6 interplay

Chae, Hye Yun; Park, Sun You; Jha, Sonam; Gupta, Sunil; Kim, Mi-Kyung; Ha, Eunyoung; Seo, Young Ho

doi:10.1016/j.ejmech.2022.114582

Cited by 15 publications

(4 citation statements)

References 52 publications

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“…Vitamin K3 (2-methyl-naphthoquinone) was also found to induce the acetylation of α-tubulin at a lower micromolar concentration but it is selective toward both HDAC6 and HDAC8 [ 238 ]. Recent research conducted by Hye Yun Chae et al established the α-tubulin-acetylating property of ‘compound 6e’ via HDAC6 inhibition in addition to Hsp90 inhibition [ 239 ]. Molecules with a diphenyl-azetidin-2-one scaffold seem to possess dual hHDAC6/hHDAC8 inhibition properties and hence increase α-tubulin acetylation [ 240 ].…”

Section: Therapeutic Strategies For Enhancing Tubulin Acetylationmentioning

confidence: 99%

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Naren

Samim

Tryphena

et al. 2023

Transl Neurodegener

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The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule (MT)-mediated axonal transport system. This mechanistically regulated system delivers cargos (proteins, mRNAs and organelles such as mitochondria) back and forth from the soma to the synapse. Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde (from the soma to the synapse) and retrograde (from the synapse to the soma) commute of the cargos, respectively. Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications (PTMs) of α- and β-tubulin heterodimers, core components constructing the MTs. Occurring within the lumen of MTs, K40 acetylation of α-tubulin via α-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible, which in turn promotes their lifespan. The movement of various motor proteins, including kinesin-1 (responsible for axonal mitochondrial commute), is enhanced by this PTM, and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions, including Alzheimer’s disease and Parkinson’s disease (PD). PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels. Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question, our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD. The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored. Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it. Graphical abstract

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Section: Therapeutic Strategies For Enhancing Tubulin Acetylationmentioning

confidence: 99%

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Naren

Samim

Tryphena

et al. 2023

Transl Neurodegener

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“…Hsp90s are drug targets in cancer therapy, but most Hsp90 inhibitors failed in clinical trials due to liver, ocular and cardiac toxicities [ 43 , 44 ]. Chae and his colleagues tried to address the existing interplay between Hsp90 and HDAC, as HDAC is believed to be vital for the development of resistance towards Hsp90 inhibitors, suggesting that the dual inhibition of Hsp90 and HDAC might overcome the issues that single inhibition of Hsp90 pose ( Figure 4 ) [ 45 , 46 ]. Computational drug design was initialized based on already existing inhibitors, such as onalespib, ganetespib, tubastatin-a and their known pharmacophores, to synthesize a novel HDAC6/Hsp90 inhibiting hybrid 13 .…”

Section: Hybrids Of Natural Products With Small Moleculesmentioning

confidence: 99%

Recent Advances in Natural Product-Based Hybrids as Anti-Cancer Agents

et al. 2022

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Cancer is one of the top leading causes of death worldwide. It is a heterogenous disease characterized by unregulated cell proliferation and invasiveness of abnormal cells. For the treatment of cancer, natural products have been widely used as a source of therapeutic ingredients since ancient times. Although natural compounds and their derivatives have demonstrated strong antitumor activity in many types of cancer, their poor pharmacokinetic properties, low cell selectivity, limited bioavailability and restricted efficacy against drug-resistant cancer cells hinder their wide clinical application. Conjugation of natural products with other bioactive molecules has given rise to a new field in drug discovery resulting to the development of novel, bifunctional and more potent drugs for cancer therapy to overcome the current drawbacks. This review discusses multiple categories of such bifunctional conjugates and highlights recent trends and advances in the development of natural product hybrids. Among them, ADCs, PDCs, ApDCs, PROTACs and AUTOTACs represent emerging therapeutic agents against cancer.

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“…HDACs, as a whole, facilitate the elimination of acetylation from lysine residues in target proteins [ 30 , 38 ]. They play a critical role in regulating cell function, not only by removing acetyl groups from lysine residues on core histones, leading to tighter chromatin and reduced gene expression [ 14 ], but also by deacetylating non-histone proteins such as the tumor suppressor p53 [ 39 – 41 ], STAT3 [ 42 ], HSP90 [ 43 ], and NF-κB [ 44 ]. This action significantly affects these proteins' function, interactions, and stability, influencing various cellular activities [ 45 ] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Exploring the role of histone deacetylase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future perspectives

Pu,

Liu,

Wang

et al. 2024

Exp Hematol Oncol

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Histone deacetylase inhibitors (HDACis) are a significant category of pharmaceuticals that have developed in the past two decades to treat multiple myeloma. Four drugs in this category have received approval from the U.S. Food and Drug Administration (FDA) for use: Panobinonstat (though canceled by the FDA in 2022), Vorinostat, Belinostat and Romidepsin. The efficacy of this group of drugs is attributed to the disruption of many processes involved in tumor growth through the inhibition of histone deacetylase, and this mode of action leads to significant anti-multiple myeloma (MM) activity. In MM, inhibition of histone deacetylase has many downstream consequences, including suppression of NF-κB signaling and HSP90, upregulation of cell cycle regulators (p21, p53), and downregulation of antiapoptotic proteins including Bcl-2. Furthermore, HDACis have a variety of direct and indirect oxidative effects on cellular DNA. HDAC inhibitors enhance normal immune function, thereby decreasing the proliferation of malignant plasma cells and promoting autophagy. The various biological effects of inhibiting histone deacetylase have a combined or additional impact when used alongside other chemotherapeutic and targeted drugs for multiple myeloma. This helps to decrease resistance to treatment. Combination treatment regimens that include HDACis have become an essential part of the therapy for multiple myeloma. These regimens incorporate drugs from other important classes of anti-myeloma agents, such as immunomodulatory drugs (IMiDs), conventional chemotherapy, monoclonal antibodies, and proteasome inhibitors. This review provides a comprehensive evaluation of the clinical efficacy and safety data pertaining to the currently approved histone deacetylase inhibitors, as well as an explanation of the crucial function of histone deacetylase in multiple myeloma and the characteristics of the different histone deacetylase inhibitors. Moreover, it provides a concise overview of the most recent developments in the use of histone deacetylase inhibitors for treating multiple myeloma, as well as potential future uses in treatment.

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Design, synthesis, and biological evalution of bifunctional inhibitors against Hsp90-HDAC6 interplay

Cited by 15 publications

References 52 publications

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Recent Advances in Natural Product-Based Hybrids as Anti-Cancer Agents

Exploring the role of histone deacetylase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future perspectives

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