Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011 – present)

Żak, Krzysztof; Pęcak, Aleksandra; Ryś, Barbara; Władyka, Benedykt; Dömling, Alexander; Weber, Lutz; Holak, Tad A.; Dubin, Grzegorz

doi:10.1517/13543776.2013.765405

Cited by 61 publications

(59 citation statements)

References 43 publications

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“…The trans configuration of two substituted phenyl rings was found to be critical for improved MDM2 binding affinity [74]. The newly developed enantiomer MI-773-01 displayed 10 times higher binding affinity against MDM2 than MI-773 did.…”

Section: 1 Spiro-pyrrolidinyl-based Inhibitorsmentioning

confidence: 98%

“…Novartis has explored several small molecular scaffolds such as 3-imidazolylindoles, substituted dihydroimidazole derivatives, tetrasubstituted heteroaryl compounds, and substituted isoquinolinones and quinazolinones as inhibitors of MDM2 and/or MDMX [74]. Though many of these new MDM2 inhibitors were capable of inhibiting tumor growth to a great extent in xenograft models of human cancer, most of these MDM2 inhibitors were unable to achieve complete tumor regression and none of them showed enough antitumor activity in animal models of human cancer to progress into clinical development [74].…”

Section: Small Molecules As Inhibitors Of Mdm2-p5interactionmentioning

confidence: 99%

“…The first candidate from Sanofi, SAR405838 (H in Fig. 2), has completed a phase I trial for patients with advanced cancer prescreening with wild-type p53 for its safety, tolerability, pharmacokinetics, and biological activity [74].…”

Section: Small Molecules As Inhibitors Of Mdm2-p5interactionmentioning

confidence: 99%

“…The MI series, originally designed by the Wang group at the University of Michigan, has been further developed by Ascenta Therapeutics and licensed by Sanofi-Aventis [74]. A review on strategies for the enantioselective synthesis of various spiro-oxindoles was reported by Ball-Jones et al [91].…”

Section: 1 Spiro-pyrrolidinyl-based Inhibitorsmentioning

confidence: 99%

“…A more potent analogue of MI-888 called MI-773 was designed by optimization of the amide side chain of MI-888 [74,100]. The trans configuration of two substituted phenyl rings was found to be critical for improved MDM2 binding affinity [74].…”

Section: 1 Spiro-pyrrolidinyl-based Inhibitorsmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: 1 Spiro-pyrrolidinyl-based Inhibitorsmentioning

confidence: 98%

Section: Small Molecules As Inhibitors Of Mdm2-p5interactionmentioning

confidence: 99%

Section: Small Molecules As Inhibitors Of Mdm2-p5interactionmentioning

confidence: 99%

Section: 1 Spiro-pyrrolidinyl-based Inhibitorsmentioning

confidence: 99%

Section: 1 Spiro-pyrrolidinyl-based Inhibitorsmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2016

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Targeting tumor suppressor genes for cancer therapy

Liu

Han

et al. 2015

BioEssays

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Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain-of-function mutations, in general, has been productive. However, it has been a major challenge to use standard pharmacologic approaches to target loss-of-function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics.

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Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors

et al. 2018

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Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small‐molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild‐type tumors; however, it also revealed dose‐limiting hematological toxicities and drug‐induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less‐frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro‐oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96 MDM2 . The designed molecules required the targeted synthesis of structurally complex spiro[indole‐3,2′‐pyrrolo[2,3‐ c ]pyrrole]‐2,4′‐diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI‐0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on‐target adverse effects.

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Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011 – present)

Cited by 61 publications

References 43 publications

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

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

Targeting tumor suppressor genes for cancer therapy

Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors

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