Non peptidic small molecular inhibitors of the p53-MDM2 interaction

Gohil, Chiragkumar J.; Noolvi, Malleshappa N.

doi:10.18231/j.ijpca.2019.019

Cited by 5 publications

(3 citation statements)

References 6 publications

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“…They mapped it by using the synthetic peptide libraries derived from the N-terminal region of p53. 12 The most active peptide obtained from this study (figure 5), was having the 28 folds greater MDM2 inhibitory property than the wild type p53-derived peptide. Peptides based MDM2 inhibitors have a structural similarity with the p53 sequence, so it easily permits the entry into the cells.…”

Section: Peptide Inhibitorsmentioning

confidence: 68%

Chemical classification of MDM2 inhibitors

Gohil

Noolvi²,

Patel³

et al. 2021

IJPCA

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MDM2 inhibitors class of anti-neoplastic drugs has been evolve after the successful discovery of the nutlins and other potent inhibitors. MDM2 inhibitors can specifically target the tumour cells in the body, by selectively reactivating the inhibited p53 function in the tumour cells.None of the compound of this class has been entered into the market till date, all are under clinical trials. Hence, various researcher classifies them according to their p53 topology mimetic property and as per their peptide type or non-peptide type.Synthetic peptide type of inhibitors can mimic the conformation of p53 helix. Whereas, small organic molecule (non-peptide) type of MDM2 inhibitors have been further subdivided as Non α-helix mimetics (small molecule inhibitors) and α-helix mimetics. In a line with synthetic inhibitors, many potent MDM2 inhibitors are derived from the natural origin (marine, fungus). Therefore, keeping in a view of all these characteristics, here we have classified them as per best of our knowledge.

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Section: Peptide Inhibitorsmentioning

confidence: 68%

Chemical classification of MDM2 inhibitors

Gohil

Noolvi²,

Patel³

et al. 2021

IJPCA

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“…The crystal structure of MDM2 linked to the transactivation domain of p53 reveals that MDM2 possesses a deep hydrophobic pocket that is filled by three side chains of the helical region of p53. [9] Therefore, the existence of this type of hydrophobic pocket on MDM2 has led to the hypothesis that this interaction can be suppressed by employing small compounds that resemble the three side chains of the p53 helix and can bind to the three pockets on MDM2. [10,11] If we design a small molecule (non-peptidic) that can engage with p53 binding pockets of MDM2 (3 pocket binding), we can suppress the interaction between p53 and MDM2.…”

Section: Mdm2 Inhibitorsmentioning

confidence: 99%

Untitled

2023

IJPBA

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Cancer is arise by inhibition of cell killing apoptosis process. Specific protein-protein interaction is responsible for the inhibition of apoptosis in the body. In this study, novel heterocyclic compounds (1,3,4-thiadiazole based) were synthesized. Synthesized compounds were successfully characterized by physical and spectral methods. And biological activity of the synthesized compounds was evaluated by cell-based assays. MTT assay was performed to determine the anti-neoplastic activity of the synthesized compounds. Moreover, a potency of the synthesized compounds was derived by IC 50 value. In an assay (in vitro), the synthesized compound induced the apoptosis in the cancer cell line. Hence, it will be proven as a potential anticancer agent.

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“…A number of MDM2 inhibitors, were designed based upon the Nutlin template (Figure 4). Using the ligand-based drug design approach, we can design the MDM2 inhibitors, which have the structural features the same as the nutlins 17 .…”

Section: Ligand-based Drug Designmentioning

confidence: 99%

Review of Design Approaches and Clinical Progress of Mdm2 Inhibitors

Gohil¹,

Noolvi²,

Patel³

et al. 2021

Int. Res. J. Pharm.

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Activation of the oncogenes and inhibition of the apoptotic function of the p53 protein is a gateway for the cancer genesis. Interaction of the MDM2 protein with p53 protein is responsible for the inhibition of the p53 function. Inhibiting the p53-MDM2 interaction by drug will lead to the p53 release in the cancer cells. And can restart the apoptosis in the cancer cell. Computational methods successfully used for the design and development of the new, potent MDM2 inhibitors. Researchers and pharma companies used rational approach like target-based drug design or ligand-based drug design to develop the novel MDM2 inhibitors. The number of MDM2 inhibitors, has been designed by the computer-aided drug design and in-silico studies. In clinical studies, MDM2 inhibitors are led by RG7112. RG7112 completed its phase-1 trials in 2016, and recently it is under phase-2 trials. Along with RG7112, the number of potent MDM2 inhibitors entered the clinical trials successfully. It indicates the successful development of this class (MDM2 inhibitors). MDM2 inhibitors were found very effective in various studies for the treatment of various kinds of cancers. They have good selectivity for the tumor cells over the normal cells. It induced the dose dependent cell cycle arrest only; in the normal cells. In studies, MDM2 inhibitors successfully detached the p53 protein from the MDM2 protein. And restart the cell-killing function of the p53 protein in the cancer cells. Hence, MDM2 inhibitors can selectively kill the cancer cells over the normal cells.

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Non peptidic small molecular inhibitors of the p53-MDM2 interaction

Cited by 5 publications

References 6 publications

Chemical classification of MDM2 inhibitors

Chemical classification of MDM2 inhibitors

Untitled

Review of Design Approaches and Clinical Progress of Mdm2 Inhibitors

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