Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy

Zhang, Zhuming; Ding, Qianqian; Liu, Jinjun; Zhang, Jing; Jiang, Nan; Chu, Xin‐Jie; Bartkovitz, David; Luk, Kin-chun; Janson, Cheryl A.; Tovar, Christian; Filipovic, Zoran; Higgins, Brian; Glenn, Kelli; Packman, Kathryn; Vassilev, Lyubomir T.; Graves, Bradford

doi:10.1016/j.bmc.2014.05.072

Cited by 50 publications

(39 citation statements)

References 42 publications

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“…Other MDM2 inhibitors were shown to enhance sensitivity to radiation in human xenografts [38, 39]. In addition to confirming our data using other in vivo models, future studies will include testing of such combinations, as well as the evaluation of more potent MDM2 inhibitors including those in clinical trials (RG7388) [40, 41]. …”

Section: Discussionsupporting

confidence: 58%

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Verreault

Schmitt

Goldwirt

et al. 2016

Clinical Cancer Research

101

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Rationale p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. Methods We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCLs), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. Results MDM2-amplified PDCLs were 44 times more sensitive than TP53 mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 μM vs 21.9 μM). MDM4 amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 μM), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 μM). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. Conclusion These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2 amplified models suggests that additional markers of response to MDM2 inhibitors must be identified.

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Section: Discussionsupporting

confidence: 58%

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Verreault

Schmitt

Goldwirt

et al. 2016

Clinical Cancer Research

101

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“…In an alternative approach, starting from the oxindole (7), a de-novo design hit, structure-based design suggested a spirooxindole scaffold similar to 5 ( Figure 5) [28]. Structural features taken from 6b were incorporated into the new scaffold giving RG8994 (8), which exhibited excellent MDM2 binding affinity, cellular activity and PK profile, comparable with 6b.…”

Section: Rg7388 Seriesmentioning

confidence: 99%

Small-Molecule MDM2-p53 Inhibitors: Recent Advances

2015

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Potent and selective small-molecule inhibitors of the p53-MDM2 interaction intended for the treatment of p53 wild-type tumors have been designed and optimized in a number of chemical series. This review details recent disclosures of compounds in advanced optimization and features key series that have given rise to clinical trial candidates. The structure-activity relationships for inhibitor classes are discussed with reference to x-ray structures, and common structural features are identified.

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“…The fact that even more novel MDM2:p53 inhibitors have been discovered based on RG7112 and RG7388, a series of spiroindolinones with RO5353, RO2468, and RO8994 as lead compounds, provides testimony that the field of developing small molecule p53 activators continues to burgeon (Z. Zhang, X. J. Chu, et al, 2014; Z. Zhang, Q. Ding, et al, 2014).…”

Section: Small Molecule Wild-type P53 Activatorsmentioning

confidence: 99%

Reviving the guardian of the genome: Small molecule activators of p53

Nguyen

Liao

Zeng

et al. 2017

Pharmacology & Therapeutics

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The tumor suppressor p53 is one of the most important proteins for protection of genomic stability and cancer prevention. Cancers often inactivate it by either mutating its gene or disabling its function. Thus, activating p53 becomes an attractive approach for the development of molecule-based anti-cancer therapy. The past decade and half have witnessed tremendous progress in this area. This essay offers readers with a grand review on this progress with updated information about small molecule activators of p53 either still at bench work or in clinical trials.

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Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy

Cited by 50 publications

References 42 publications

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Small-Molecule MDM2-p53 Inhibitors: Recent Advances

Reviving the guardian of the genome: Small molecule activators of p53

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