p53 α-Helix mimetics antagonize p53/MDM2 interaction and activate p53

Chen, Lihong; Yin, Hang; Farooqi, Bilal; Sebti, Saı̈d M.; Hamilton, Andrew D.; Chen, Jiandong

doi:10.1158/1535-7163.mct-04-0342

Cited by 90 publications

(78 citation statements)

References 24 publications

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“…However, compound 43 was inactive in a cell-based assay. 103 Another terphenyl derivative, 45, had modest activity in the FP assay and similar activity in a p53/ MDM2 ELISA (IC 50 ¼ 20 lM). This compound was able to activate transcription by p53 in cells at a 30 lM concentration.…”

Section: Terphenylsmentioning

confidence: 98%

Targeting protein–protein interactions: Lessons from p53/MDM2

2007

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The tremendous challenge of inhibiting therapeutically important protein–protein interactions has created the opportunity to extend traditional medicinal chemistry to a new class of targets and to explore nontraditional strategies. Here we review a widely studied system, the interaction between tumor suppressor p53 and its natural antagonist MDM2, for which both traditional and nontraditional approaches have been reported. This system has been a testing ground for novel proteomimetic scaffold‐based strategies, i.e., for attempts to mimic the recognition surface displayed by a folded protein with unnatural oligomers. Retroinverso peptides, peptoids, terphenyls, β‐hairpins, p‐oligobenzamides, β‐peptides, and miniproteins have all been explored as inhibitors of the p53/MDM2 interaction, and we focus on these oligomer‐based efforts. Traditional approaches have been successful as well, and we briefly review small molecule inhibitors along with other strategies for reactivation of the p53 pathway, for comparison with oligomer‐ based approaches. We close with comments on an emerging dichotomy among protein–protein interaction targets. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88: 657–686, 2007.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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Section: Terphenylsmentioning

confidence: 98%

Targeting protein–protein interactions: Lessons from p53/MDM2

2007

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“…[6][7][8][9][10][11][12][13][14][15][16][17][18][19] In cells with functional p53, the p53 activity is primarily inhibited through direct and tonic interaction with the MDM2 protein. [20][21][22] Treatment of various tumor cells with inhibitors of the MDM2-p53 interaction results in rising p53 levels and subsequent induction of cell-cycle arrest and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia

Saddler¹,

Ouillette²,

Kujawski³

et al. 2008

Blood

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Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and remains incurable with conventional therapies. Patients with relapsed or resistant CLL have a significantly shortened lifespan. MDM2 inhibitors have been developed and may have significant potential in the treatment of CLL. Clinical development of these compounds would be aided through knowledge of molecular predictors of activity. To understand determinants of sensitivity or resistance to MDM2 inhibitor therapy in CLL, we comprehensively analyzed a large cohort of CLL patient-derived samples for response to MDM2 inhibition and correlated these responses with clinically important biomarkers. Furthermore, we employed high-density single nucleotide polymorphism (SNP) arrays to analyze genomewide changes of copy number and allele status, including that of p53. The results of these studies conclusively demonstrate that p53 status is the major determinant of response to MDM2 inhibitors in CLL. Additional defects in the p53 regulatory cascade do not appear operational in this leukemia. Further, we identify a novel subgroup of patients with CLL with early progressive disease that appears particularly sensitive to MDM2 inhibitor treatment. These data provide definitive evidence for target-specific and predictive activity and a rationale to proceed with this potentially important class of compounds in the treatment of CLL. IntroductionChronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world, and is characterized by a highly variable clinical course. 1,2 Treatment of CLL is reserved for symptomatic patients or patients in advanced clinical stage. Despite improvements in response rates using chemoimmunotherapy combinations, CLL remains incurable, and patients refractory to fludarabine or patients who have suffered multiple disease relapses have a poor outlook. [3][4][5] Therefore, novel therapeutics are needed to advance the outlook for afflicted patients.Inhibitors of murine double minute 2 (Mdm2) represent a novel therapeutic approach. [6][7][8][9][10][11][12][13][14][15][16][17][18][19] In cells with functional p53, the p53 activity is primarily inhibited through direct and tonic interaction with the MDM2 protein. [20][21][22] Treatment of various tumor cells with inhibitors of the MDM2-p53 interaction results in rising p53 levels and subsequent induction of cell-cycle arrest and apoptosis. For poorly understood reasons, nonmalignant cells appear relatively resistant to MDM2 inhibition. 23,24 In CLL, in contrast to many solid tumors, p53 is mutated in only about 10% of patients at presentation and in 10% to 30% of patients with pretreated disease. [25][26][27][28] Thus, small-molecule inhibitors that block the MDM2-p53 interaction could represent a new therapeutic strategy for the treatment of most patients with CLL.Human cancers are biologically heterogeneous and respond nonuniformly to therapeutic intervention. Therefore, understanding the molecular mechanisms underlying cancer susceptibili...

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“…The choice of the phenyldipyridyl scaffold over the diphenyl, terphenyl, and other scaffolds suggested by Jacoby, 86 Hamilton and coworkers, [87][88][89][90] and others 91 was based on extensive Density Functional Theory analyses of candidate scaffolds ( Figure 10) by Che et al 60 This study provided an understanding for the design of helix mimetics, and why the simple concept of moving the side chains from the interacting surface of a peptide helix to the aromatic scaffold is not straightforward (Figure 11). …”

Section: Combinatorial Library Of Helix Mimeticsmentioning

confidence: 99%

“…87,88,[92][93][94][95] Back to the Future: Ribonuclease A 267 des, 104,105 organic bicyclic rings such as benzodiazepines, 106 and metal complexes of chiral pentaazacrowns. 107 Arnold et al 102 used EPL to construct RNase analogs in which synthetic peptide fragments 95-124 were ligated with expressed RNase 1-94.…”

Section: Figure 10mentioning

confidence: 99%

Back to the future: Ribonuclease A

2008

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Pancreatic ribonuclease A (EC 3.1.27.5, RNase) is, perhaps, the best‐studied enzyme of the 20th century. It was isolated by René Dubos, crystallized by Moses Kunitz, sequenced by Stanford Moore and William Stein, and synthesized in the laboratory of Bruce Merrifield, all at the Rockefeller Institute/University. It has proven to be an excellent model system for many different types of experiments, both as an enzyme and as a well‐characterized protein for biophysical studies. Of major significance was the demonstration by Chris Anfinsen at NIH that the primary sequence of RNase encoded the three‐dimensional structure of the enzyme. Many other prominent protein chemists/enzymologists have utilized RNase as a dominant theme in their research. In this review, the history of RNase and its offspring, RNase S (S‐protein/S‐peptide), will be considered, especially the work in the Merrifield group, as a preface to preliminary data and proposed experiments addressing topics of current interest. These include entropy–enthalpy compensation, entropy of ligand binding, the impact of protein modification on thermal stability, and the role of protein dynamics in enzyme action. In continuing to use RNase as a prototypical enzyme, we stand on the shoulders of the giants of protein chemistry to survey the future. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 259–277, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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p53 α-Helix mimetics antagonize p53/MDM2 interaction and activate p53

Cited by 90 publications

References 24 publications

Targeting protein–protein interactions: Lessons from p53/MDM2

Targeting protein–protein interactions: Lessons from p53/MDM2

Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia

Back to the future: Ribonuclease A

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