Structure-Based Design of Spiro-oxindoles as Potent, Specific Small-Molecule Inhibitors of the MDM2−p53 Interaction

Ding, Ke; Lu, Yuele; Nikolovska‐Coleska, Zaneta; Wang, Guoping; Qiu, Su; Shangary, Sanjeev; Gao, Wei; Qin, Dajun; Stuckey, Jeanne A.; Krajewski, Krzysztof; Roller, Peter P.; Wang, Shaomeng

doi:10.1021/jm051122a

Cited by 639 publications

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“…(Dudkina and Lindsley, 2007). Shaomeng Wang's lab used structure-based design to identify a particularly promising set of spiro-oxindoles and quinolinols as new potent and specific non-peptide, small molecule Mdm2 antagonists (Ding et al, 2006;Lu et al, 2006). Both these classes of compounds have shown promising results in cell lines, inducing cellular responses in a p53-dependent manner.…”

Section: Targeting the P53 -Mdm2 Interactionmentioning

confidence: 99%

Updates on p53: modulation of p53 degradation as a therapeutic approach

2008

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Section: Targeting the P53 -Mdm2 Interactionmentioning

confidence: 99%

Updates on p53: modulation of p53 degradation as a therapeutic approach

2008

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“…Interestingly, distinct p53-activating drugs have strongly divergent effects. For example, Nutlin-3 3 and MI-219 4 mainly induce G1 and G2 arrest, resulting in depletion of S-phase cells, whereas induction of apoptosis by these compounds varies greatly between cell lines. On the other hand, RITA does not induce G1 arrest, but in general is more capable of inducing apoptosis.…”

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Chk2 mediates RITA-induced apoptosis

et al. 2011

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Reactivation of the p53 tumor-suppressor protein by small molecules like Nutlin-3 and RITA (reactivation of p53 and induction of tumor cell apoptosis) is a promising strategy for cancer therapy. The molecular mechanisms involved in the responses to RITA remain enigmatic. Several groups reported the induction of a p53-dependent DNA damage response. Furthermore, the existence of a p53-dependent S-phase checkpoint has been suggested, involving the checkpoint kinase Chk1. We have recently shown synergistic induction of apoptosis by RITA in combination with Nutlin-3, and we observed concomitant Chk2 phosphorylation. Therefore, we investigated whether Chk2 contributes to the cellular responses to RITA. Strikingly, the induction of apoptosis seemed entirely Chk2 dependent. Transcriptional activity of p53 in response to RITA required the presence of Chk2. A partial rescue of apoptosis observed in Noxa knockdown cells emphasized the relevance of p53 transcriptional activity for RITAinduced apoptosis. In addition, we observed an early p53-and Chk2-dependent block of DNA replication upon RITA treatment. Replicating cells seemed more prone to entering RITA-induced apoptosis. Furthermore, the RITA-induced DNA damage response, which was not a secondary effect of apoptosis induction, was strongly attenuated in cells lacking p53 or Chk2.In conclusion, we identified Chk2 as an essential mediator of the cellular responses to RITA.

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“…The p53 protein regulates cell cycle, repairs DNA, and initiates apoptosis (Ding et al, 2006). Thus, p53's role as a tumour suppressor is well known and studied.…”

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“…Thus, p53's role as a tumour suppressor is well known and studied. p53 is mutated in paediatric malignancies in approximately 50% of cases; however, the frequency of mutations differs among tumour types (Taylor et al, 2000;Ding et al, 2006). The remaining tumours that retain wild-type p53 develop alternative mechanisms that disrupt normal function and lead to malignant proliferation (Tovar et al, 2006).…”

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“…MI-63, a novel, non-peptide small-molecule inhibitor, shows promise as an inhibitor of the p53 -MDM2 interaction in prostate cancer cells with wild-type p53; however, it has not been tested in paediatric sarcomas (Ding et al, 2006). Previously, non-peptide small-molecule inhibitors of the p53 -MDM2 interaction have targeted three, well-described, hydrophobic residues (Phe19, Trp23, and Leu26); however, the MI63 design includes a fourth residue (Leu22) that has an important role in p53 binding to MDM2 (Lin et al, 1994;Kussie et al, 1996;Ding et al, 2006).…”

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MI-63: A novel small-molecule inhibitor targets MDM2 and induces apoptosis in embryonal and alveolar rhabdomyosarcoma cells with wild-type p53

et al. 2009

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BACKGROUND: Interruption of the role of p53s as a tumour suppressor by MDM2 may be one of the mechanisms by which cancer cells evade current therapy. Blocking the inhibition of wild-type p53 by MDM2 in cancer cells should reactivate p53's tumour suppressor functions and enhance current cancer treatments. MI-63 is a novel non-peptide small molecule that has shown strong binding affinity (K i ¼ 3 nM) for MDM2; however, its effects on paediatric cancer cells and the specific mechanism of tumour suppressor reactivation have not been evaluated. METHODS: Rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma, expresses either wild-type or mutant p53 protein. We examined the inhibitory effects of MI-63 in embryonal RMS (ERMS) and alveolar RMS (ARMS) cell lines expressing wildtype or mutated p53. RESULTS: Treatment with MI-63 reduced cell viability by 13.4% and by o1%, respectively, at 72 h in both RH36 and RH18 cell lines expressing wild-type p53. In contrast, RH30 and RD2 cells expressing p53 mutants are resistant to MI-63 treatment. An increased expression of p53, p21 WAF1 , and Bax protein was observed after treatment with MI-63 in RMS cells with wild-type p53, and apoptosis was confirmed by cleaved PARP and caspase-3 expression. However, RD2 and RH30 RMS cells, as well as human normal skeletal muscle cells, showed a minimal increase in p53 signalling and no induction of cleaved PARP and caspase-3. MI-63 was compared with Nutlin-3, a known MDM2 inhibitor, and was found to be more potent in the inhibition of cell proliferation/viability. Further, synergy was observed when MI-63 was used in combination with doxorubicin. CONCLUSION: These results indicate that MI-63 is a potent therapeutic agent for RMS cells expressing wild-type p53 protein.

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Structure-Based Design of Spiro-oxindoles as Potent, Specific Small-Molecule Inhibitors of the MDM2−p53 Interaction

Cited by 639 publications

References 20 publications

Updates on p53: modulation of p53 degradation as a therapeutic approach

Updates on p53: modulation of p53 degradation as a therapeutic approach

Chk2 mediates RITA-induced apoptosis

MI-63: A novel small-molecule inhibitor targets MDM2 and induces apoptosis in embryonal and alveolar rhabdomyosarcoma cells with wild-type p53

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