Potent and Orally Active Small-Molecule Inhibitors of the MDM2−p53 Interaction

Yu, Shanghai; Qin, Dajun; Shangary, Sanjeev; Chen, Jianyong; Wang, Guoping; Ding, Ke; McEachern, Donna; Qiu, Su; Nikolovska‐Coleska, Zaneta; Miller, Rebecca S.; Kang, Sanmao; Yang, Dajun; Wang, Shaomeng

doi:10.1021/jm901400z

Cited by 170 publications

(119 citation statements)

References 22 publications

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“…MI-219 binds to MDM2 with K i = 5 nM and has an oral bioavailability of 65% in rats and a much improved exposure in pharmacokinetic studies in rats. Detailed investigation of MI-219 was performed in vitro and in vivo to determine its therapeutic potential and its molecular mechanism of action [56]. MI-219 was shown to induce activation of p53 by blocking the MDM2-p53 protein-protein interaction in cells expressing wild-type p53 but failed to induce p53 activation in cells expressing mutated p53, consistent with its expected mode of action as a potent and specific MDM2 inhibitor.…”

Section: Structure-based Design Of Spirooxindole-containing Compoundsmentioning

confidence: 73%

“…However, MI-63 only has a modest oral bioavailability (10%) in pharmacokinetic studies in rats. Efforts were made to improve the oral bioavailability of MI-63, which resulted in MI-219 [56]. MI-219 binds to MDM2 with K i = 5 nM and has an oral bioavailability of 65% in rats and a much improved exposure in pharmacokinetic studies in rats.…”

Section: Structure-based Design Of Spirooxindole-containing Compoundsmentioning

confidence: 99%

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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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Section: Structure-based Design Of Spirooxindole-containing Compoundsmentioning

confidence: 73%

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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“…These MDM2-amplified GBM patients have a worse progression-free and total survival and decreased response to therapy [41]. In the subset of tumors with MDM2 amplification, MDM2 could potentially be targeted with inhibitor compounds, allowing the otherwise normal p53 to function [42][43][44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis

et al. 2017

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According to the recently updated World Health Organization (WHO) classification (2016), grade II-III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II-III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II-III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II-III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

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“…The series demonstrated clear SAR and the better analogs showed remarkable potency given their small size and the ability to occupy only two of the three surface subpockets in the p53 binding region. The presence of the 6-chloro-indole group provided the expectation that the binding mode could be predicted because this same group is used in some of the known MDM2 antagonists (36).…”

Section: Discussionmentioning

confidence: 99%

Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization

Graves

Thompson

Xia

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

203

207

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Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo-and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMXoverexpressing cancers.T he tumor suppressor p53 is a powerful growth-suppressive and proapoptotic protein tightly controlled by its negative regulators: murine double minute (MDM)2 and MDMX (1, 2). These proteins bind p53 with their structurally similar N-terminal domains and effectively inhibit p53 transcriptional activity (1, 3). They both possess a RING (really interesting new gene) domain in their C termini, but it is only functional in MDM2, which serves as a specific E3 ligase and main regulator of p53 stability (4, 5). Despite its RING domain, MDMX does not have an intrinsic ligase activity and does not affect directly p53 stability (6). However, MDMX can enhance ligase activity of MDM2 toward p53 by forming MDM2/MDMX heterodimers (7,8). It has been reported that the MDM2/MDMX complex is responsible for polyubiquitination of p53, whereas MDM2 alone primarily induces monoubiquitination (9). Targeted disruption of MDM2/MDMX heterocomplexes is embryonic-lethal in mice, suggesting that complex formation is essential for p53 regulation in vivo (10). On the other hand, MDM2 can also ubiquitinate MDMX and is, therefore, responsible for its stability as well (11,12). MDM2 is a transcriptional target of p53, and both proteins form an autoregulatory feedback loop by which they mutually control their cellular levels (13).The functional relationship between MDM2 and MDMX is still being refined at the molecular level, but it is well established that these two negative regulators play a critical role in controlling p53 tumor-suppressor function in normal cells (2,14). This is why they are frequently overproduced through gene amplification and/or overexpression in tumors that retain wildtype p53 (14). Therefore, antagonizing the binding of MDM2 and MDMX to p53 is expected to restore p53 function and may offer a strategy for cancer therapy (15). Recently identified small-molecule inhibitors of the p53-MDM2 interaction have validated this approach, and the first pharmacological MDM2 antagonists ar...

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Potent and Orally Active Small-Molecule Inhibitors of the MDM2−p53 Interaction

Cited by 170 publications

References 22 publications

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

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

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis

Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization

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