Fortifying p53 - beyond Mdm2 inhibitors.
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ABSTRACT:
SUBMITTER: Sriraman A
PROVIDER: S-EPMC5076439 | biostudies-literature | 2016 Sep
REPOSITORIES: biostudies-literature
Publications
Fortifying p53 - beyond Mdm2 inhibitors.
Sriraman Anusha A Li Yizhu Y Dobbelstein Matthias M
Aging 20160901 9
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Project description:The protein-protein interaction (PPI) between p53 and its negative regulator MDM2 comprises one of the most important and intensely studied PPI's involved in preventing the initiation of cancer. The interaction between p53 and MDM2 is conformation-based and is tightly regulated on multiple levels. Due to the Angstrom level structural insight there is a reasonable understanding of the structural requirements needed for a molecule to bind to MDM2 and successfully inhibit the p53/MDM2 interaction. The current review summarizes the binding characteristics of the different disclosed small molecules for inhibition of MDM2 with a co-crystal structure. Synthetic access to these compounds as well as their derivatives are described in detail.
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Project description:Based on a combination of an Ugi four component reaction and a ring closing metathesis, a library of novel artificial macrocyclic inhibitors of the p53-MDM2 interaction was designed and synthesized. These macrocycles, alternatively to stapled peptides, target for the first time the large hydrophobic surface area formed by Tyr67, Gln72, His73, Val93, and Lys94 yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using fluorescence polarization (FP) assay and 1H-15N two-dimensional HSQC nuclear magnetic resonance experiments.
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Project description:p53, encoded by the tumor suppressor gene TP53, is one of the most important tumor suppressor factors in vivo and can be negatively regulated by MDM2 through p53-MDM2 negative feedback loop. Abnormal p53 can be observed in almost all tumors, mainly including p53 mutation and functional inactivation. Blocking MDM2 to restore p53 function is a hotspot in the development of anticancer candidates. Till now, nine MDM2 inhibitors with different structural types have entered clinical trials. However, no MDM2 inhibitor has been approved for clinical application. This review focused on the discovery, structural modification, preclinical and clinical research of the above compounds from the perspective of medicinal chemistry. Based on this, the possible defects in MDM2 inhibitors in clinical development were analyzed to suggest that the multitarget strategy or targeted degradation strategy based on MDM2 has the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors and improve their anti-tumor activity, providing certain guidance for the development of agents targeting the p53-MDM2 interaction.
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Project description:It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation. Although numerous studies indicate that the MDM2 E3 ligase activity, as well as the protein-protein interaction between p53 and MDM2, is the major focus for this regulation, emerging evidence suggests that the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7) plays a critical role. Furthermore, HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes. In this review, we discuss the advances of this dynamic pathway and the contributions of positive and negative regulators affecting HAUSP activity. We also highlight the roles of HAUSP in cancer justifying the production of the first generation of HAUSP inhibitors.
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Project description:Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2-p53 protein-protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase clinical trials for the treatment of human cancers. Here, we review the design, synthesis, properties, preclinical, and clinical studies of these clinical-stage MDM2 inhibitors.
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Project description: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%.
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Project description:Proteins that limit the activity of the tumour suppressor protein p53 are increasingly being targeted for inhibition in a variety of cancers. In addition to the development of small molecules, there has been interest in developing constrained (stapled) peptide inhibitors. A stapled peptide ALRN_6924 that activates p53 by preventing its interaction with its negative regulator Mdm2 has entered clinical trials. This stapled peptide mimics the interaction of p53 with Mdm2. The chances that this peptide could bind to other proteins that may also interact with the Mdm2-binding region of p53 are high; one such protein is the CREB binding protein (CBP)/p300. It has been established that phosphorylated p53 is released from Mdm2 and binds to p300, orchestrating the transcriptional program. We investigate whether molecules such as ALRN_6924 would bind to p300 and, to do so, we used molecular simulations to explore the binding of ATSP_7041, which is an analogue of ALRN_6924. Our study shows that ATSP_7041 preferentially binds to Mdm2 over p300; however, upon phosphorylation, it appears to have a higher affinity for p300. This could result in attenuation of the amount of free p300 available for interacting with p53, and hence reduce its transcriptional efficacy. Our study highlights the importance of assessing off-target effects of peptide inhibitors, particularly guided by the understanding of the networks of protein-protein interactions (PPIs) that are being targeted.
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Project description:Reactivation of p53 by release of the functional protein from its inhibition by MDM2 provides an efficient, nongenotoxic approach to a wide variety of cancers. We present the cocrystal structures of two complexes of MDM2 with inhibitors based on 6-chloroindole scaffolds. Both molecules bound to a distinct conformational state of MDM2 with nM-?M affinities. In contrast to other structurally characterized antagonists, which mimic three amino acids of p53 (Phe19, Trp23, and Leu26), the compounds induced an additional hydrophobic pocket on the MDM2 surface and unveiled a four-point binding mode. The enlarged interaction interface of the inhibitors resulted in extension of small molecules binding toward the "lid" segment of MDM2 (residues 19-23)--a nascent element that interferes with p53 binding. As supported by protein engineering and molecular dynamics studies, employing these unstable elements of MDM2 provides an efficient and yet unexplored alternative in development of MDM2-p53 association inhibitors.
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Project description:This review presents the last decade of studies on the synthesis of various types of small-molecule inhibitors of the p53- Mouse double minute 2 homolog (MDM2) protein-protein interaction. The main focus is placed on synthetic approaches to such molecules, their cytotoxicity, and MDM2 binding characteristics.
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Project description:The p53 protein is the cell's principal bastion of defense against tumor-associated DNA damage. Commonly referred as a "guardian of the genome", p53 is responsible for determining the fate of the cell when the integrity of its genome is damaged. The development of tumors requires breaching this defense line. All known tumor cells either mutate the p53 gene, or in a similar number of cases, use internal cell p53 modulators, Mdm2 and Mdmx proteins, to disable its function. The release of functional p53 from the inhibition by Mdm2 and Mdmx should in principle provide an efficient, nongenotoxic means of cancer therapy. In recent years substantial progress has been made in developing novel p53-activating molecules thanks to several reported crystal structures of Mdm2/x in complex with p53-mimicking peptides and nonpeptidic drug candidates. Understanding the structural attributes of ligand binding holds the key to developing novel, highly effective, and selective drug candidates. Two low-molecular-weight compounds have just recently progressed into early clinical studies.
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