A novel dual HDAC and HSP90 inhibitor, MPT0G449, downregulates oncogenic pathways in human acute leukemia in vitro and in vivo

Wu, Yi; Chao, Min Wu; Tu, Huang Ju; Chen, Liang Chieh; Hsu, Kai Cheng; Liou, Jing Ping; Yang, Congrong; Yen, Shih Chung; HuangFu, Wei Chun; Pan, Shiow‐Lin

doi:10.1038/s41389-021-00331-0

Cited by 18 publications

(9 citation statements)

References 74 publications

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“…Numerous studies have demonstrated that inhibiting HDAC6 and Hsp90 simultaneously has a synergistic anticancer effect [ 37 , 38 , 39 ]. This study aimed to identify natural compounds targeting the HDAC6 and Hsp90 proteins using an in silico approach.…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

et al. 2023

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Breast cancer (BC) is one of the main types of cancer that endangers women’s lives. The characteristics of triple-negative breast cancer (TNBC) include a high rate of recurrence and the capacity for metastasis; therefore, new therapies are urgently needed to combat TNBC. Dual targeting HDAC6 and Hsp90 has shown good synergistic effects in treating metastatic TNBC. The goal of this study was to find potential HDAC6 and Hsp90 dual inhibitors. Therefore, several in silico approaches have been used. An e-pharmacophore model generation based on the HDAC6-ligand complex and subsequently a pharmacophore-based virtual screening on 270,450 natural compounds from the ZINC were performed, which resulted in 12,663 compounds that corresponded to the obtained pharmacophoric hypothesis. These compounds were docked into HDAC6 and Hsp90. This resulted in the identification of three compounds with good docking scores and favorable free binding energy against the two targets. The top three compounds, namely ZINC000096116556, ZINC000020761262, and ZINC000217668954, were further subjected to ADME prediction and molecular dynamic simulations, which showed promising results in terms of pharmacokinetic properties and stability. As a result, these three compounds can be considered potential HDAC6 and Hsp90 dual inhibitors and are recommended for experimental evaluation.

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Section: Resultsmentioning

confidence: 99%

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

et al. 2023

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“…MPT0G449 exhibited cytotoxicity on two AML cells higher than the pan-HDAC inhibitor SAHA and the Hsp90 inhibitor 17-AAG used as controls. The results proved that the ligand targets both HDAC and Hsp90, induces cell cycle arrest at the G2 phase, and is able to suppress oncogenic signalling in acute leukemia cells [178]. One of the most popular scaffolds employed in the development of dual inhibitors of Hsp90-HDAC6 is represented by (iso)indolines.…”

Section: Available Dual Hdac-hsp90 Inhibitorsmentioning

confidence: 90%

Dual Targeting Strategies on Histone Deacetylase 6 (HDAC6) and Heat Shock Protein 90 (Hsp90)

Bonanni

Citarella

Moi

et al. 2022

CMC

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: The design of multi-target drugs acting simultaneously on multiple signaling pathways is a growing field in medicinal chemistry, especially for the treatment of complex diseases such as cancer. Histone deacetylase 6 (HDAC6) is an established anticancer drug target involved in tumor cells transformation. Being an epigenetic enzyme at the interplay of many biological processes, HDAC6 has become an attractive target for polypharmacology studies aimed at improving therapeutic efficacy of anticancer drugs. For example, the molecular chaperone Heat shock protein 90 (Hsp90) is a substrate of HDAC6 deacetylation, and several lines of evidence demonstrate that simultaneous inhibition of HDAC6 and Hsp90 promote synergistic antitumor effects on different cancer cell lines, highlighting the potential benefits of developing a single molecule endowed with multi-target activity. This review will summarize the complex interplay between HDAC6 and Hsp90, providing also useful hints for multi-target drug design and discovery approaches in this field. To this end, crystallographic structures of HDAC6 and Hsp90 complexes will be extensively reviewed in the light of discussing binding pockets features and pharmacophore requirements and providing useful guidelines for the design of dual inhibitors. The few examples of multi-target inhibitors obtained so far, mostly based on chimeric approaches, will be summarized and put into context. Finally, the main features of HDAC6 and Hsp90 inhibitors will be compared, and ligand- and structure-based strategies potentially useful for the development of small molecular weight dual inhibitors will be proposed and discussed.

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“…The hydroxamate group is critical for efficient binding of the small molecule inhibitor to the enzyme. However, given the multi-drug resistance and the dearth of potent HDAC inhibitor with high efficacy, development of dual HDAC inhibitors has evolved as a lucrative approach to cancer treatment [ 39 , 40 , 41 ]. Several reports came to light in the past decade highlighting the pharmacological significance of the fusion of the quinazoline pharmacophore with various FDA approved HDAC inhibitors to harness the synergistic effects of these two pharmacophoric units.…”

Section: Synergistic Effect Of the Dual Inhibition/hybrid Approachmentioning

confidence: 99%

Quinazoline Based HDAC Dual Inhibitors as Potential Anti-Cancer Agents

Dhuguru

Ghoneim

2022

Molecules

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Cancer is the most devastating disease and second leading cause of death around the world. Despite scientific advancements in the diagnosis and treatment of cancer which can include targeted therapy, chemotherapy, endocrine therapy, immunotherapy, radiotherapy and surgery in some cases, cancer cells appear to outsmart and evade almost any method of treatment by developing drug resistance. Quinazolines are the most versatile, ubiquitous and privileged nitrogen bearing heterocyclic compounds with a wide array of biological and pharmacological applications. Most of the anti-cancer agents featuring quinazoline pharmacophore have shown promising therapeutic activity. Therefore, extensive research is underway to explore the potential of these privileged scaffolds. In this context, a molecular hybridization approach to develop hybrid drugs has become a popular tool in the field of drug discovery, especially after witnessing the successful results during the past decade. Histone deacetylases (HDACs) have emerged as an important anti-cancer target in the recent years given its role in cellular growth, gene regulation, and metabolism. Dual inhibitors, especially based on HDAC in particular, have become the center stage of current cancer drug development. Given the growing significance of dual HDAC inhibitors, in this review, we intend to compile the development of quinazoline based HDAC dual inhibitors as anti-cancer agents.

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A novel dual HDAC and HSP90 inhibitor, MPT0G449, downregulates oncogenic pathways in human acute leukemia in vitro and in vivo

Cited by 18 publications

References 74 publications

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

Dual Targeting Strategies on Histone Deacetylase 6 (HDAC6) and Heat Shock Protein 90 (Hsp90)

Quinazoline Based HDAC Dual Inhibitors as Potential Anti-Cancer Agents

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