Discovery and Optimization of Chromenotriazolopyrimidines as Potent Inhibitors of the Mouse Double Minute 2−Tumor Protein 53 Protein−Protein Interaction

Allen, John G.; Bourbeau, Matthew P.; Wohlhieter, G. Erich; Bartberger, Michael D.; Michelsen, Klaus; Hungate, Randall W.; Gadwood, Robert C.; Gaston, Rick; Evans, Bruce J. W.; Mann, Larry W; Matison, Michael E; Schneider, Stephen E.; Huang, Xin; Yu, Dongyin; Andrews, Paul S.; Reichelt, Andreas; Long, Alexander; Yakowec, P.; Yang, Evelyn; Lee, Tani Ann; Oliner, Jonathan D.

doi:10.1021/jm900681h

Cited by 135 publications

(82 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although smallmolecule antagonists of the p53-MDM2 interaction such as nutlins (36,37) or MDM2 inhibitors (4,38), have been developed in the past few years, the development of novel molecular targeting methods for MDM2 is a remaining need for cancer therapy. Our data suggest that the restoration of p53 activity by targeting MDM2 using miR-340 may be an effective approach in PCa therapy.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-340 inhibits prostate cancer cell proliferation and metastasis by targeting the MDM2-p53 pathway

Huang

Tang

et al. 2015

Oncology Reports

View full text Add to dashboard Cite

Abstract. An increasing number of studies have demonstrated the important role of microRNAs (miRNAs) in modulating cancer progression and metastasis, but the mechanisms by which miRNAs regulate prostate cancer (PCa) tumorigenesis remain poorly understood. In the present study, we found that miR-340 may act as a tumor suppressor based on our finding that it was significantly downregulated in PCa tumor tissues and cell lines. Moreover, the expression of miR-340 was found to be correlated with the inhibition of cell proliferation, migration and invasion in vitro, and had a suppressive effect on tumor growth in a xenograft mouse model as well. The suppressive effect of miR-340 overexpression was observed in cell lines DU145 and BPH-1 which express wild-type (WT) p53. However, in the p53-null PC-3 cell line, the suppressive effect was not found, indicating that miR-340 may play a critical role in the p53 pathway. Further investigation revealed that mouse double minute 2 (MDM2), an important regulator of p53, was targeted by miR-340 through the direct binding to the 3'UTR of MDM2, which inhibited MDM2 translation. In addition, miR-340 expression stabilized p53 protein levels which caused an increase in p21 expression but a decrease in the anti-apoptotic protein, BCL-2, in the p53 WT cell lines. Moreover, the miR-340-mediated inhibition of cell progression was mitigated by re-expressing MDM2 in the stable miR-340-overexpressing PCa cell line, which harbors WT p53. Our findings suggest that miR-340 may function as a novel tumor suppressor in PCa through the MDM2-p53 pathway by directly targeting MDM2, which may be a promising miRNA-targeted therapy for PCa.

show abstract

Section: Discussionmentioning

confidence: 99%

MicroRNA-340 inhibits prostate cancer cell proliferation and metastasis by targeting the MDM2-p53 pathway

Huang

Tang

et al. 2015

Oncology Reports

View full text Add to dashboard Cite

show abstract

“…The structure of MDM2 complexed to a smallmolecule inhibitor of MDM2-53 interaction, chromenotriazolopyrimidine (PDB: 3JZK), 20 demonstrates that the compound and the p53 peptide share the same binding cavity and induce similar conformation changes upon binding (Fig. 4b and c), implying that similar mechanisms may be involved in the binding of these two molecules.…”

Section: Interleukin-2mentioning

confidence: 99%

Protein Hot Spots: The Islands of Stability

Kuttner

Engel

2012

Journal of Molecular Biology

View full text Add to dashboard Cite

“…Scientists from Amgen also reported a class of chromenotriazolopyrimidine compounds as MDM2 inhibitors [68]. One extensively modified compound (D in Fig.…”

Section: Small Molecules As Inhibitors Of Mdm2-p5interactionmentioning

confidence: 99%

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

et al. 2016

View full text Add to dashboard Cite

As a result of the toxicity of currently available anticancer drugs and the inefficiency of chemotherapeutic treatments, the design and discovery of effective and selective antitumor agents continues to be a hot topic in organic medicinal chemistry. Targeted therapy is a newer type of cancer treatment that uses drugs designed to interfere with specific molecules necessary for tumor growth and progression. This review explains the mechanism of regulation of p53 (tumor suppressor protein) by MDM2 and illustrates the role of targeting p53-MDM2 protein-protein interaction using small molecules as a new cancer therapeutic strategy. Spirocyclic oxindoles or spiro-oxindoles, with a rigid heterocyclic ring fused at the 3-position of the oxindole core with varied substitution around it, are the most efficacious class of small molecules which inhibit cell proliferation and induce apoptosis in cancer cells, leading to complete tumor growth regression without affecting activities of normal cells. In this review, we present a comprehensive account of the systematic development of and recent progress in diverse spiro-oxindole derivatives active as potent selective inhibitors of p53-MDM2 interaction with special emphasis on spiro-pyrrolidinyl oxindoles (the MI series), their mechanism of action, and structure-activity relationship. This review will help in understanding the molecular mechanism of p53 reactivation by spiro-oxindoles in tumor tissues and also facilitates the design and exploration of more potent analogues with high efficacy and low side effects for the treatment of cancer. Recent progress in spiro-oxindole derivatives as potent small molecule inhibitors of p53-MDM2 interaction, useful as anticancer agents, is described with reference to their mechanism of action and structure-activity relationship.

show abstract

Discovery and Optimization of Chromenotriazolopyrimidines as Potent Inhibitors of the Mouse Double Minute 2−Tumor Protein 53 Protein−Protein Interaction

Cited by 135 publications

References 49 publications

MicroRNA-340 inhibits prostate cancer cell proliferation and metastasis by targeting the MDM2-p53 pathway

MicroRNA-340 inhibits prostate cancer cell proliferation and metastasis by targeting the MDM2-p53 pathway

Protein Hot Spots: The Islands of Stability

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

Contact Info

Product

Resources

About