A Potent Small-Molecule Inhibitor of the MDM2–p53 Interaction (MI-888) Achieved Complete and Durable Tumor Regression in Mice

Zhao, Yujun; Yu, Shanghai; Sun, Wei; Liu, Liu; Lu, Jianfeng; McEachern, Donna; Shargary, Sanjeev; Bernard, Denzil; Li, Xiaoqin; Zhao, Ting C.; Zou, Peng; Sun, Duxin; Wang, Shaomeng

doi:10.1021/jm4005708

Cited by 249 publications

(163 citation statements)

References 21 publications

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“…19 Second, a methoxy para-benzoic acid moiety in RG7388 ("C" in Figure 1) was transferred to RO8994, in which a slight modification was made by converting the terminal carboxylic acid to a carboxamide moiety. In contrast to aliphatic groups, 19,20 the aromatic group ("C") proved to be critical for both RG7388 and RO8994 as it stabilized the molecule metabolically, significantly improved cellular potency/selectivity, PK profiles, and in vivo efficacy. 14,15 On the basis of the crystal structures, the 3-chloro-2-fluorophenyl group binds to the Leu26 pocket on MDM2, while the neopentyl group occupies the Phe19 pocket ( Figure 1).…”

Section: * S Supporting Informationmentioning

confidence: 99%

Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

Zhang

Chu

Liu

et al. 2014

ACS Med. Chem. Lett.

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The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidinebased inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.KEYWORDS: MDM2, p53, wild-type, small molecule, apoptosis, cancer T umor suppressor p53 is a potent transcription factor that is activated in response to cellular stress and regulates downstream genes controlling cell cycle arrest and apoptosis. 1−4 Dysfunction of the p53 pathway is the most frequent alteration observed in human cancers. 5 MDM2 is the primary negative regulator of p53 through binding to its transactivation domain and promoting proteosomal degradation. 6−8 In tumor cells with wild-type p53 (∼50%), reactivation of the p53 pathway by inhibition of MDM2 with small molecules has been considered as potentially an attractive novel therapeutic approach for cancer treatment. 9,10 Currently, several smallmolecule MDM2 inhibitors including RG7112 and RG7388 (Figure 1) are undergoing clinical evaluations. 11−14 To maximize the chance of success in the clinic and derisk any potential idiopathic toxicity associated with specific chemotypes, continued research efforts are required to expand chemodiversity and identify potent and selective MDM2 antagonists with desirable in vitro ADMET and in vivo pharmacokinetic properties. Here we report the discovery of RO5353 and RO2468, two new highly potent and selective MDM2 inhibitors with potential for clinical development.Our exploration initially led to the identification of a potent and selective MDM2 inhibitor RO8994 (Figure 1), which was found to be highly efficacious against established human tumor xenografts in nude mouse models. 15 Two key structural elements of RG7388 were preserved in RO8994. First, it was established that the stereochemical configuration of the pyrrolidine core structure in which the two aryl rings ("A" and "B") adopt a "Trans" orientation was very important for optimal binding to MDM2. 14 The architecture of spiroindolinone-3,3′-pyrrolidine series (as exemplified by MI-219) was first reported by Ding et al. 16−18 Consistent with our findings, this group recently published their latest findings in which the original stereochemistry was found to be unstable and

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Section: * S Supporting Informationmentioning

confidence: 99%

Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

Zhang

Chu

Liu

et al. 2014

ACS Med. Chem. Lett.

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“…It was discovered that compound 3, which has a different stereochemistry from MI-17, MI-63, and MI-219, has a very high affinity to MDM2 (K i < 1 nM). Further optimization of the pharmacokinetic properties of 3 yielded MI-888, which has a K i value of 0.44 nM and Small-molecule MDM2 and MDMX inhibitors is highly potent and selective in inhibition of tumor cell growth in cancer cell lines with wild-type p53 over those with mutated or deleted p53 [58]. MI-888 has an excellent oral bioavailability in rats and is capable of achieving complete and durable tumor regression in two animal models of human cancer upon daily oral administration.…”

Section: Structure-based Design Of Spirooxindole-containing Compoundsmentioning

confidence: 99%

Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics

Zhao¹,

Bernard²,

Wang³

2013

Biodiscovery

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Inactivation of the function of tumor suppressor p53 is common in human cancers. In approximately half of human cancers, the tumor suppressor function of p53 is inactivated by deletion or mutation of TP53, the gene encoding p53 protein. In the remaining 50% of human cancers, p53 tumor suppressor function can be effectively inhibited by oncoprotein MDM2 or its homolog MDMX. Since inhibition of p53 by MDM2 or MDMX protein is mediated by their direct interaction with p53, small-molecule inhibitors designed to block the MDM2-p53 or MDMX-p53 protein-protein interaction (MDM2 or MDMX inhibitors) can activate p53 in tumor cells retaining wild-type p53. In the last few years, several classes of potent, selective, and efficacious small molecule MDM2 inhibitors have been designed and developed, and six such compounds are being evaluated in clinical trials as new anticancer drugs. Additionally, non-peptide, small-molecule MDMX inhibitors have been reported. We review herein the design and development of potent small-molecule MDM2 and MDMX inhibitors.

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“…Complete tumor regression was observed in all the animals after 7 days of dosing with MI-888. Even 26 days after the last dose, all mice treated with MI-888 at 200 mg/kg remained tumor-free [99]. There was no significant weight loss or other signs of toxicity for all the mice treated during the entire experiment.…”

Section: 1 Spiro-pyrrolidinyl-based Inhibitorsmentioning

confidence: 89%

“…7). MI-888 is capable of achieving complete and durable tumor regression in two animal models of human cancer, i.e., SJSA-1 osteosarcoma and acute lymphoblastic leukemia tumor xenograft models, upon daily oral administration [99]. When MI-888 was administered at 100 and 200 mg/kg via oral gavage daily for 3 weeks, rapid and complete tumor regression was achieved.…”

Section: 1 Spiro-pyrrolidinyl-based Inhibitorsmentioning

confidence: 99%

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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A Potent Small-Molecule Inhibitor of the MDM2–p53 Interaction (MI-888) Achieved Complete and Durable Tumor Regression in Mice

Cited by 249 publications

References 21 publications

Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics

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

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