Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors

Dong, Guoqiang; Chen, Wei; Wang, Xia; Yang, Xinglin; Xu, Tao; Wang, Pei; Zhang, Wannian; Rao, Yu; Miao, Chao‐Yu; Sheng, Chunquan

doi:10.1021/acs.jmedchem.7b00467

Cited by 94 publications

(73 citation statements)

References 59 publications

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“…The NAMPT inhibitor (NAMPTi) FK866, which entered clinical trials but whose development has been limited by dose‐limiting thrombocytopenia, has been reported to synergistically improve the activity of HDACi. Starting from these evidence, Chen et al developed dual NAMPT/HDAC inhibitors, by connecting the N ‐(3‐(1 H ‐imidazol‐1‐yl)propyl)‐5‐thiazolecarboxamide moiety contained in the novel NAMPT inhibitor 76 (Figure ) with an amidopolimethylene‐hydroxamate tail, able to inhibit HDACs . Among them, 77 was the most potent compound in term of enzymatic and cellular activity (IC 50 values: 15 [NAMPT], 2 [HDAC1], 6.8 [HDAC2], 0.67 [HDAC3], 12 000 [HDAC4], 0.64 [HDAC6], and 204 [HDAC8] nM) (Figure ).…”

Section: The Mtdl Approachmentioning

confidence: 99%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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Section: The Mtdl Approachmentioning

confidence: 99%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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“…For many proteins implicated in cancer, structural biology information has proven invaluable for understanding their functional implications as well as discovering novel therapeutic modalities. [49][50][51][52] Unfortunately, it is difficult to study mucins structurally by traditional methods. Crystallographic methods falter because of the sheer size of mucins (up to 14 000 kDa), extensive variation in the number of tandem repeats within the VNTR (up to 120), sequence variation, and inability to clone, express, and purify fully folded and glycosylated forms.…”

Section: Intrinsically Disordered Proteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Presence and structure‐activity relationship of intrinsically disordered regions across mucins

et al. 2020

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Abbreviations: AMOP, adhesion-associated domain in MUC4 and other proteins domain; CH, charge hydropathy; D 2 P 2 , database of disordered protein predictions; ECM, extracellular matrix; EGF, epidermal growth factor-like domain; IDP, intrinsically disordered protein; IDR, intrinsically disordered region; MoRF, molecular recognition feature; NIDO, nidogen-like domain; PPI, protein-protein interaction; PTM, posttranslational modification; PTS sequence, proline, threonine and serine sequence; SEA, sea-urchin sperm protein enterokinase and agrin module; TM, transmembrane; VNTR, variable number of tandem repeat domain; vWD, von Willebrand factor D domain. AbstractMany members of the mucin family are evolutionarily conserved and are often aberrantly expressed and glycosylated in various benign and malignant pathologies leading to tumor invasion, metastasis, and immune evasion. The large size and extensive glycosylation present challenges to study the mucin structure using traditional methods, including crystallography. We offer the hypothesis that the functional versatility of mucins may be attributed to the presence of intrinsically disordered regions (IDRs) that provide dynamism and flexibility and that the IDRs offer potential therapeutic targets. Herein, we examined the links between the mucin structure and function based on IDRs, posttranslational modifications (PTMs), and potential impact on their interactome. Using sequence-based bioinformatics tools, we observed that mucins are predicted to be moderately (20%-40%) to highly (>40%) disordered and many conserved mucin domains could be disordered. Phosphorylation sites overlap with IDRs throughout the mucin sequences. Additionally, the majority of predicted O-and N-glycosylation sites in the tandem repeat regions occur within IDRs and these IDRs contain a large number of functional motifs, that is, molecular recognition features (MoRFs), which directly influence protein-protein interactions (PPIs).This investigation provides a novel perspective and offers an insight into the complexity and dynamic nature of mucins. K E Y W O R D Sintrinsically disordered protein, glycoprotein, protein-protein interaction, protein structure 1940 | CARMICHEAL Et AL.

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“…Also, Dong et al . have reported dual NAMPT/HDAC inhibitors but this time the research group used the 2‐aminobenzamide as the ZBG instead of hydroxamate.…”

Section: Design Of Dual Nampt/hdac Inhibitorsmentioning

confidence: 99%

“…Also, Dong et al 140 Also, further studies that determine its safety and pharmacokinetic profile are required to illustrate its safety and bioavailability.…”

Section: Design Of Dual Nampt/hdac Inhibitorsmentioning

confidence: 99%

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

Hesham

Lasheen

Abouzid

2018

Medicinal Research Reviews

122

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Recently, molecular hybridization paradigm became an interesting and smart way to defeat the multifaceted cancer disease by a single molecular entity that acts via several mechanisms just like a magic bullet. Also, HDAC is an important epigenetic target in drug discovery, and the HDAC inhibitors showed successful pattern as cytotoxic agents. Because of their flexible structure activity relationship, it was easy to link them to other anticancer scaffolds. So, many dual action HDAC inhibitors have been developed and most of these hybrids have higher potency than the constituting parents in fighting of the cancer cells. This review describes potential applications of chimeric HDAC inhibitors, which simultaneously modulate not only HDAC but also multiple targets, in treatment of relapsing and drug-resistant cancers. We have nearly collected most of the reported dual action HDAC inhibitors yet to provide a comprehensive guide for the drug discovery process for developing more efficient anticancer agents.

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Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors

Cited by 94 publications

References 59 publications

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Presence and structure‐activity relationship of intrinsically disordered regions across mucins

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

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