Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction (original) (raw)
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Chemical Biology <html_ent glyph="@amp;" ascii="&"/> Drug Design, 2006
Small molecule antagonists of protein-protein interactions represent a particular challenge for pharmaceutical discovery. One approach to finding molecules that can disrupt these interactions is to seek mimics of common protein structure motifs. We present an analysis of how molecules based on the 1,4-benzodiazepine-2,5-dione scaffold serve to mimic the side-chains presented by the hydrophobic face of two turns of an a-helix derived from the tumor suppressor protein p53, and thus antagonize the HDM2-p53 protein-protein binding interaction.
8-Triazolylpurines: Towards Fluorescent Inhibitors of the MDM2/p53 Interaction
PLOS ONE, 2015
Small molecule nonpeptidic mimics of α-helices are widely recognised as protein-protein interaction (PPIs) inhibitors. Protein-protein interactions mediate virtually all important regulatory pathways in a cell, and the ability to control and modulate PPIs is therefore of great significance to basic biology, where controlled disruption of protein networks is key to understanding network connectivity and function. We have designed and synthesised two series of 2,6,9-substituted 8-triazolylpurines as α-helix mimetics. The first series was designed based on low energy conformations but did not display any biological activity in a biochemical fluorescence polarisation assay targeting MDM2/p53. Although solution NMR conformation studies demonstrated that such molecules could mimic the topography of an α-helix, docking studies indicated that the same compounds were not optimal as inhibitors for the MDM2/p53 interaction. A new series of 8-triazolylpurines was designed based on a combination of docking studies and analysis of recently published inhibitors. The best compound displayed low micromolar inhibitory activity towards MDM2/p53 in a biochemical fluorescence polarisation assay. In order to evaluate the applicability of these compounds as biologically active and intrinsically fluorescent probes, their absorption/emission properties were measured. The compounds display fluorescent properties with quantum yields up to 50%.
European Journal of Medicinal Chemistry, 2011
A series of thio-benzodiazepine p53eMDM2 inhibitors were designed and synthesized based on the principle of bioisosterism. Most of the thio-benzodiazepines had nanomolar to micromolar affinity toward MDM2. Particularly, compounds 8a (K i ¼ 0.52 mM) and 8f (K i ¼ 0.32 mM) showed binding activity comparable to the positive drug nutlin-3a (K i ¼ 0.23 mM). Meanwhile, compound 8j exhibited excellent antitumor activity against the U-2 OS human osteosarcoma cell line with an IC 50 value of 1.06 mM, which was about 23 times higher than that of nutlin-3a. The docking model also successfully predicted that this class of compounds mimicked three p53 critical residues binding to MDM2. The thio-benzodiazepines represent a promising class of non-peptide inhibitors of the p53eMDM2 interaction.
Asian Journal of Pharmaceutical and Clinical Research
Objective: P53 protein is well known for its role in cell cycle regulation and induction of apoptosis. This protein is degraded by MDM2 mediated proteolysis. Inhibition of interaction between p53 and MDM2 has been recognized as a most potential and selective target for development of novel anticancer agents. Recently, several molecules entered in the clinical trial study for the treatment of various types of cancers are based on inhibition of interaction between p53-MDM2. Therefore, in this study, a novel dihydropyridine based molecules were designed as p53-MDM2 inhibitor, and their anticancer activity (including reference) was determined in comparison with most active anticancer agent and inactive anticancer agents in National Cancer Institute database using “Cancer IN” server.Methods: In this work, a novel dihydropyrimidinone based lead (L11) on the basis of molecular docking study, predicted IC50, anticancer activity, and toxicity profile were designed. Lead L11 was obtained af...
Bioorganic Medicinal Chemistry Letters, 2014
Introducing an aryl moiety to our previous pyrrolidone scaffold by molecule fusing strategy afforded two sets of isopropylether-pyrrolidone and a-phenylethylamine-pyrrolidone derivatives. Two novel compounds 8b and 8g of the latter serial showed potent p53-MDM2 inhibitory activities with K i values of 90 nM which were three-time higher than that of the parent compound. We also confirmed compound 8b can activate p53 proteins in lung cancer A549 cells. The results offered us valuable information for further lead optimization.
Cancer is a class of diseases characterized by out-of-control cell growth. Cancer is a leading cause of death worldwide.The p53 tumor suppressor is one of the principal mediators of cell-cycle arrest and the activation of apoptosis in response to cellular injuries . In normal unstressed cells, p53 is regulated by a feedback loop with the negative regulator protein MDM2 (murine double -minute clone 2, referred to as human double -minute clone 2, HDM2 , in humans) . A well -known mechanism for the loss of wild -type p53 activity in cancer cells is the overexpression of MDM2.The murine double minute 2 (MDM2) protein facilitates G1 to S phase transition by activation of E2F-1 and can enhance cell survival by suppressing wild-type p53 function.Murine DM2 (MDM2) protein is overexpressed in a variety of neoplasms, including acute leukemias, myelodysplastic syndrome, chronic lymphocytic leukemia and lymphomas , multiple myelomas etc. Blocking the MDM2-p53 interaction to reactivate the p53 function is a promising cancer therapeutic strategy. Activation of the p53 protein protects the organism against the propagation of cells that carry damaged DNA with potentially oncogenic mutations. This can be attained by designing a molecule which can bind to P53 transactivation site of Mdm2 and further this Mdm2 protein cannot bind with P53 .The aim of present study is designing a small molecule(antagonist) having capability to bind with the over expressed Mdm2 protein and blocking its path to bind with p53 tumour suppressor protein that is having sufficient absorption and free of hepatotoxicity and carcinogenicity.
Potent and Orally Active Small-Molecule Inhibitors of the MDM2− p53 Interaction
Journal of medicinal …, 2009
We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a Ki value of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.
Discovery of a new small-molecule inhibitor of p53–MDM2 interaction using a yeast-based approach
Biochemical Pharmacology, 2013
The virtual screening of a library of xanthone derivatives led us to the identification of potential novel MDM2 ligands. The activity of these compounds as inhibitors of p53-MDM2 interaction was investigated using a yeast phenotypic assay, herein developed for the initial screening. Using this approach, in association with a yeast p53 transactivation assay, the pyranoxanthone (3,4-dihydro-12hydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one) (1) was identified as a putative smallmolecule inhibitor of p53-MDM2 interaction. The activity of the pyranoxanthone 1 as inhibitor of p53-MDM2 interaction was further investigated in human tumor cells with wild-type p53 and overexpressed MDM2. Notably, the pyranoxanthone 1 mimicked the activity of known p53 activators, leading to p53 stabilization and activation of p53dependent transcriptional activity. Additionally, it led to increased protein levels of p21 and Bax, and to caspase-7 cleavage. By computational docking studies, it was predicted that, like nutlin-3a, a known small-molecule inhibitor of p53-MDM2 interaction, pyranoxanthone 1 binds to the p53-binding site of MDM2. Overall, in this work, a novel small-molecule inhibitor of p53-MDM2 interaction with a xanthone scaffold was identified for the first time. Besides its potential use as molecular probe and possible lead to develop anticancer agents, the pyranoxanthone 1 will pave the way for the structure-based design of a new class of p53-MDM2 inhibitors.