Rational design and optimization of novel 4-methyl quinazoline derivatives as PI3K/HDAC dual inhibitors with benzamide as zinc binding moiety for the treatment of acute myeloid leukemia

Zhang, Kehui; Huang, Rui; Ji, Ming; Lin, Songwen; Lai, Fangfang; Wu, Deyu; Tian, Hua; Bi, Jinhui; Peng, Shouguo; Hu, Jiaqi; Sheng, Li; Li, Yan; Chen, Xiaoguang; Xu, Heng

doi:10.1016/j.ejmech.2023.116015

Cited by 3 publications

(2 citation statements)

References 47 publications

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“…Despite favourable antiproliferative activities against a broad panel of cancer cell lines, these compounds only showed limited in vivo activities largely due to their poor pharmacokinetic properties. Therefore, the same research team incorporated the benzamide moiety as the zinc binding group and, by means of molecular docking and QSAR studies, obtained two potent PI3K/HDAC dual inhibitors for the treatment of acute myeloid leukemia with improved pharmacokinetic properties [268].…”

Section: Molecular Modelingmentioning

confidence: 99%

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Curcio,

Rocca,

Alcaro

et al. 2024

Pharmaceuticals

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Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson–Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.

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Section: Molecular Modelingmentioning

confidence: 99%

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Curcio,

Rocca,

Alcaro

et al. 2024

Pharmaceuticals

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show abstract

“…These inhibitors have been rigorously designed, and their efficacy has been demonstrated to surpass that of their respective single-target counterparts, owing to their superior metabolic stability. The discovery of such inhibitors is a promising advancement in the treatment of AML [ 199 ]. Medical research continues to make noteworthy strides in this regard, and it is hoped that further exploration in this area will lead to the development of more effective cancer treatments.…”

Section: Emerging Therapeutic Strategies Targeting Chromatin Modifiersmentioning

confidence: 99%

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

Nie,

Song,

Huang

et al. 2024

Mol Biomed

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The field of transcriptional regulation has revealed the vital role of chromatin modifiers in human diseases from the beginning of functional exploration to the process of participating in many types of disease regulatory mechanisms. Chromatin modifiers are a class of enzymes that can catalyze the chemical conversion of pyrimidine residues or amino acid residues, including histone modifiers, DNA methyltransferases, and chromatin remodeling complexes. Chromatin modifiers assist in the formation of transcriptional regulatory circuits between transcription factors, enhancers, and promoters by regulating chromatin accessibility and the ability of transcription factors to acquire DNA. This is achieved by recruiting associated proteins and RNA polymerases. They modify the physical contact between cis-regulatory factor elements, transcription factors, and chromatin DNA to influence transcriptional regulatory processes. Then, abnormal chromatin perturbations can impair the homeostasis of organs, tissues, and cells, leading to diseases. The review offers a comprehensive elucidation on the function and regulatory mechanism of chromatin modifiers, thereby highlighting their indispensability in the development of diseases. Furthermore, this underscores the potential of chromatin modifiers as biomarkers, which may enable early disease diagnosis. With the aid of this paper, a deeper understanding of the role of chromatin modifiers in the pathogenesis of diseases can be gained, which could help in devising effective diagnostic and therapeutic interventions.

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Design, synthesis and biological evaluation of a novel PSMA–PI3K small molecule drug conjugate

Peng,

Li,

Cui

et al. 2024

RSC Med. Chem.

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Rational design and optimization of novel 4-methyl quinazoline derivatives as PI3K/HDAC dual inhibitors with benzamide as zinc binding moiety for the treatment of acute myeloid leukemia

Cited by 3 publications

References 47 publications

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

Design, synthesis and biological evaluation of a novel PSMA–PI3K small molecule drug conjugate

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