RG7112, a Small-Molecule Inhibitor of MDM2, Enhances Trabectedin Response in Soft Tissue Sarcomas

Obrador‐Hevia, Antònia; Martinez-Font, Esther; Felipe-Abrio, Irene; Calabuig, Silvia; Serra-Sitjar, Margalida; Löpez‐Guerrero, José Antonio; Ramos, Rafael; Alemany, Regina; Martin‐Broto, Javier

doi:10.3109/07357907.2015.1064534

Cited by 22 publications

(12 citation statements)

References 29 publications

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“…Besides, the synergistic effect was observed in LNCaP when combined with androgen ablation, leading to a significant tumor regression 24 . Recently, Obrador-Hevia and co-workers 35 found that RG7112 can significantly enhance the response of Trabectedin to MDM2-amplified liposarcoma cells. Clinical pharmacological studies showed that high/low-fat food and new formulation can enhance bioavailability; high-dose consecutive daily dosing for 3–5 days can yield required high drug exposures and PD effects for cancer therapy 36 .…”

Section: Development Of Mdm2/x Inhibitors For Cancer Therapymentioning

confidence: 99%

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives

Fang

Liao

2020

Acta Pharmaceutica Sinica B

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Blocking the MDM2/X–P53 protein–protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers. Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2–P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure–activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions.

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Section: Development Of Mdm2/x Inhibitors For Cancer Therapymentioning

confidence: 99%

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives

Fang

Liao

2020

Acta Pharmaceutica Sinica B

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“…When this is combined with MDM2 inhibitors, both stability and activity of p53 are increased, leading to pronounced cell death. The DNA damaging drug Trabectedin, currently used in second line for treating soft tissue sarcoma, was also reported to synergize with the MDM2 inhibitor RG7112 46 , perhaps as a result of p53 accumulation (through MDM2 inhibition) and activating p53 modifications (through DNA damage response). In preclinical investigations and cell culture, MDM2 antagonists also cooperated efficiently with mitogen-activated protein kinase kinase (MEK) or phosphatidylinositol-3 kinase (PI3K) inhibitors, BH3 mimetics, BCR-ABL antagonists, and histone deacetylase inhibitors 47 .…”

Section: Discussionmentioning

confidence: 99%

CDK4 inhibition diminishes p53 activation by MDM2 antagonists

et al. 2018

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The genes encoding MDM2 and CDK4 are frequently co-amplified in sarcomas, and inhibitors to both targets are approved or clinically tested for therapy. However, we show that inhibitors of MDM2 and CDK4 antagonize each other in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon MDM2 inhibition. Moreover, the p53 response was also attenuated when co-depleting MDM2 and CDK4 with siRNA, compared to MDM2 single knockdown. The complexes of p53 and MDM2, as well as CDK4 and Cyclin D1, physically associated with each other, suggesting direct regulation of p53 by CDK4. Interestingly, CDK4 inhibition did not reduce p53 binding or histone acetylation at promoters, but rather attenuated the subsequent recruitment of RNA Polymerase II. Taken together, our results suggest that caution must be used when considering combined CDK4 and MDM2 inhibition for patient treatment. Moreover, they uncover a hitherto unknown role for CDK4 and Cyclin D1 in sustaining p53 activity.

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“…Cell proliferation and apoptosis assays. Real-time cell proliferation and viability after treatment with doxorubicin or nilotinib, as single agents or in sequential combination, was performed on SW982 cells, using the xCELLigence System as described previously (24). Analysis of the cell cycle by flow cytometry was performed on SW872 cells as described previously (16).…”

Section: Methodsmentioning

confidence: 99%

Nilotinib as Coadjuvant Treatment with Doxorubicin in Patients with Sarcomas: A Phase I Trial of the Spanish Group for Research on Sarcoma

Alemany

Moura

Redondo

et al. 2018

Clinical Cancer Research

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Nilotinib plus doxorubicin showed to be synergistic regarding apoptosis in several sarcoma cell lines. A phase I/II trial was thus designed to explore the feasibility of nilotinib as coadjuvant of doxorubicin by inhibiting MRP-1/P-gp efflux activity. The phase I part of the study is presented here. Nilotinib 400 mg/12 hours was administered in fixed dose from day 1 to 6, and doxorubicin on day 5 of each cycle. Three dose escalation levels for doxorubicin at 60, 65, and 75 mg/m were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma, leiomyosarcoma, and unresectable/metastatic high-grade chondrosarcoma. Thirteen patients were enrolled: 7 chondrosarcoma, 4 liposarcoma, and 2 leiomyosarcoma. In 46 cycles administered, the most relevant grade 3/4 adverse effects per patient were neutropenia 54%, febrile neutropenia 15%, and asthenia 8%. No cardiac toxicity was observed. Only one dose-limiting toxicity (febrile neutropenia) was reported in the third dose level. With regard to efficacy, 1 partial response (1 liposarcoma), 9 stable diseases (5 chondrosarcoma, 2 liposarcoma, 1 leiomyosarcoma), and 3 progressive diseases (2 chondrosarcoma and 1 leiomyosarcoma) were present. and RNA expression levels decreased by 58.47-fold and 1.47-fold, respectively, on day 5 of the cycle. Combination of MRP-1/P-gp inhibitor, nilotinib, as coadjuvant with doxorubicin is feasible; it appears not to add substantial toxicity compared with doxorubicin alone. Pharmacodynamic study supports this concept. The recommended dose for the phase II part for doxorubicin was 75 mg/m .

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RG7112, a Small-Molecule Inhibitor of MDM2, Enhances Trabectedin Response in Soft Tissue Sarcomas

Cited by 22 publications

References 29 publications

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives

CDK4 inhibition diminishes p53 activation by MDM2 antagonists

Nilotinib as Coadjuvant Treatment with Doxorubicin in Patients with Sarcomas: A Phase I Trial of the Spanish Group for Research on Sarcoma

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