Challenges in the Design of Multitarget Drugs Against Multifactorial Pathologies: A New Life for Medicinal Chemistry?

Costantino, Luca; Barlocco, Daniela

doi:10.4155/fmc.12.193

Cited by 25 publications

(22 citation statements)

References 20 publications

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“…As a matter of fact, diseases with linear pathways might be well treated with single target agents. However, cancer is a disease with complex signaling networks, which means it is difficult to treat most cancers by using single classical targeted drug [2]. Combination chemotherapy can simultaneously block several key signaling pathways and create synergistic antitumor effects [3e11].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors

Zhang

Kong

Zhang

et al. 2015

European Journal of Medicinal Chemistry

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Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors

Zhang

Kong

Zhang

et al. 2015

European Journal of Medicinal Chemistry

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“…In addition, the off‐target side effects of the multitarget compounds may induce the loss of homeostasis that leads to the loss of body control on the cancer resulting in metastasis. Thus, full analysis of the network nodes in the cancer cell can aid in the selection of the appropriate interacting targets to fight this complex, multifactorial disease …”

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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“…Radiotherapy can demolish healthy cells as well as destroy cancer cells and cause treatment side effects. Many factors are responsible for the development of drug resistance: (1) one or more mutations in target proteins, (2) increase in the activity of drug efflux pumps (ATP-binding cassette superfamily), (3) decreased drug influx, and (4) transformed expression of apoptosis and anti-apoptotic proteins [2]. Chemosensitization, radiosensitization, and cancer interception are a prerequisite for the enhancement of drug activity against cancer.…”

Section: Introductionmentioning

confidence: 99%

Screening of multi-targeted natural compounds for receptor tyrosine kinases inhibitors and biological evaluation on cancer cell lines, in silico and in vitro

Singh

Bast

2015

Med Oncol

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Receptors for growth factors encompass within the superfamily of receptor tyrosine kinases and are known to regulate numerous biological processes including cellular growth, proliferation, metabolism, survival, cell differentiation and apoptosis. These receptors have recently caught the attention of the researchers as an attractive target to combat cancer owing to the evidence suggesting their over-expression in cancer cells. Therefore, we studied receptor-based molecular docking of IR (PDB; 3ETA), IGF1R (PDB; 1K3A), EGFR (PDB; 1M17), VEGFIR (PDB; 3HNG), and VEGFIIR (PDB; 2OH4) against natural compounds. Further, in vitro investigation of the biological effect of lead molecules in an array of cancer cell lines was done. All selected natural compounds were docked with the X-ray crystal structure of selected protein by employing GLIDE (Grid-based Ligand Docking with Energetics) Maestro 9.6. InterBioScreen natural compounds docked with each selected protein molecules by using GLIDE high throughput virtual screening. On the basis of Gscore, we select 20 compounds along with 68 anticancer compounds for GLIDE extra precision molecular docking. It was discovered in this study that compound epigallocatechin gallate (EGCG) yielded magnificent Gscore with IGF1R (PDB; 1K3A) and VEGFIIR (PDB; 2OH4), and protein-ligand interactions are chart out. Effect of EGCG on biological activity such as mRNA expression of selected protein, cell proliferation, oxidative stress, and cell migration was reported after the 48 h treatments in cancer cell lines. The RT-PCR densitometric bands analysis showed that compound EGCG reduced the mRNA expression of IGF1R, VEGFIIR, and mTOR at 80 μM concentration. Moreover, EGCG significantly reduced cell proliferation and ROS generation after 48 h treatments. Our result also indicated a reduction in the potential for cell migration that might show in vivo anti-metastasis activity of EGCG.

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Challenges in the Design of Multitarget Drugs Against Multifactorial Pathologies: A New Life for Medicinal Chemistry?

Abstract: The article is an editorial; it forecast that a new life in medicinal chemistry can be represented by multitarget drug design coupled with systems biolog

Cited by 25 publications

References 20 publications

Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors

Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors

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

Screening of multi-targeted natural compounds for receptor tyrosine kinases inhibitors and biological evaluation on cancer cell lines, in silico and in vitro

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