Fluorescence polarization assay and inhibitor design for MDM2/p53 interaction

Zhang, Rumin; Mayhood, Todd; Lipari, Philip; Wang, Yaolin; Durkin, James; Syto, Rosalinda; Gesell, Jennifer J.; McNemar, Charles; Windsor, William

doi:10.1016/j.ab.2004.03.009

Cited by 39 publications

(50 citation statements)

References 42 publications

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“…An X-ray crystal structure of the N-terminal domain of MDM2 bound to a 15-residue transactivation domain of p53 revealed the structural details of their complex that is mediated by the interaction of three hydrophobic residues of a p53 α-helix with a hydrophobic cleft of MDM2 18. Molecules that bind the hydrophobic cleft of MDM2 disrupt this protein—protein interaction with p53, restoring its regulatory function and inhibiting tumor growth 4,19-22…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis of Chlorofusin, Its Seven Chromophore Diastereomers, and Key Partial Structures

2008

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Chlorofusin is a recently isolated, naturally occurring inhibitor of p53−MDM2 complex formation whose structure is composed of a densely functionalized azaphilone-derived chromophore linked through the terminal amine of ornithine to a nine residue cyclic peptide. Herein we report the full details of the total synthesis of chlorofusin, resulting in the assignment of the absolute stereochemistry and reassignment of the relative stereochemistry of the complex chromophore. Condensation of each enantiomer of an azaphilone chromophore precursor with the Nδ-amine of a protected ornithinethreonine dipeptide, followed by a one-step oxidation/spirocyclization of the most reactive olefin provided all eight diastereomers of the fully elaborated chromophore−dipeptide conjugate. Comparison of the spectroscopic properties for these eight compounds and those of simpler models with that reported for the natural product allowed the full assignment of the (4R,8S,9R)-stereochemistry of the chlorofusin chromophore. The natural, but stereochemically reassigned, diastereomer of the dipeptide conjugate was incorporated in a convergent total synthesis of chlorofusin confirming the stereochemical reassignment and establishing its absolute stereochemistry. Similarly and enlisting the late stage convergent point in the total synthesis, the remaining seven diastereomers of the chromophore−dipeptide conjugates were individually incorporated into the 9-residue cyclic peptide of chlorofusin (4 steps each) providing all seven remaining possible chromophore diastereomers of the natural product.

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Section: Introductionmentioning

confidence: 99%

Total Synthesis of Chlorofusin, Its Seven Chromophore Diastereomers, and Key Partial Structures

2008

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“…In other cases, small molecules were designed de novo, directly from the peptide. In one study, a library of designed 2-phenoxybenzoyl-tryptophan derivatives was synthesized, yielding a 100 nM inhibitor [36]. The Hamilton lab utilized their terphenyl scaffold, already proven to be a generic -helical mimic, to develop a p53-MDM2 inhibitor with 1 M potency [37].…”

Section: Mdm2mentioning

confidence: 99%

Utilizing Peptide Structures As Keys For Unlocking Challenging Targets

Fry¹,

Sun²

2006

MRMC

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Three-dimensional structures of protein targets have proven to be extremely valuable for modern drug design and discovery. For cases where the structure of the protein is unattainable, such as G-protein coupled receptors (GPCRs), structural information on active ligands is still useful and helpful for deciphering the geometrical and chemical features of the active site. Peptides, constructed from easy-to-form amide backbones and featuring variable side-chains, have an inherent advantage in generating rapid quantitative structure-activity relationships (QSAR). Given the fact that peptides are natural ligands for many protein targets, structural investigation of a series of related peptides, typically carried out via nuclear magnetic resonance (NMR), can result in an accurate pharmacophore model. Such a model can be used for virtual screening, and to assist design of second-generation peptidomimetics with improved properties and design of non-peptidic leads. In this article, we will review examples in which a structural approach utilizing peptide ligands was employed to obtain a better understanding of the target active site. We will focus on cases where such information supplied guidance toward the discovery of small molecule ligands.

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“…SLiMs are widely used by higher eukaryotes to perform a variety of targeting and signaling functions [59]. The most common "receiver" domains are PDZ, PTB, SH2, and WW [60]. SLiMs adopt a variety of structures when bound to their receiver domain: an extended structure that lies in a groove (14-3-3 [61]; Rb/E7 [62]); a β-strand that augments a β-sheet (PTB [63] and PDZ [64] domains); α-helices that augment a helical bundle (FAK-paxillin [65]; β-/α-catenin [66]); or even a polyproline helix (SH3 [67]).…”

Section: Protein-peptide Interactions: a Key Mediator Of Complexity Imentioning

confidence: 99%