Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

Holzer, Philipp; Masuya, Keiichi; Furet, Pascal; Kallen, Joerg; Stachyra, Therese‐Marie; Ferretti, Stéphane; Berghausen, Joerg; Bouisset-Leonard, Michèle; Buschmann, Nicole; Pissot‐Soldermann, Carole; Rynn, Caroline; Ruetz, Stephan; Stutz, Stefan; Chêne, Patrick; Jeay, Sébastien; Gessier, François

doi:10.1021/acs.jmedchem.5b00810

Cited by 155 publications

(163 citation statements)

References 28 publications

(51 reference statements)

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“…When this injury-and stress-activated process affects acinar cells that harbor an oncogenic Kras G12D , it accelerates acquisition of malignant traits. These findings suggest that treatment of individuals who are at high risk of PDAC development with new and improved MDM2 inhibitors, currently under development (Holzer et al, 2015; Wang et al, 2014), may prevent PanIN to PDAC progression and reduce the toll of this currently incurable malignancy.…”

Section: Discussionmentioning

confidence: 95%

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

et al. 2017

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SUMMARY Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors such as chronic pancreatitis, acinar cell damage and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals.

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Section: Discussionmentioning

confidence: 95%

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

et al. 2017

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“…The majority including WM3973, were predicted sensitive to MDM2 inhibition (data not shown). The MDM2 inhibitor CGM097 (Holzer et al, 2015) moderately inhibited WM3973 tumor growth as a single agent, but ERK and MDM2 inhibition synergized potently to induce stable disease over 6 weeks of dosing (Figure 5E, left panel).…”

Section: Resultsmentioning

confidence: 99%

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

et al. 2017

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Summary Therapy of advanced melanoma has been changing dramatically. Following mutational and biological sub-classification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays, and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups.

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Section: Discussionmentioning

confidence: 99%

“…MDM2 inhibitors such as nutlin-3a [14] or NVP-CGM097 [86] act by preventing p53 binding to MDM2 and thus MDM2-targeted proteasomal degradation of p53 [14] . NVP-CGM097 thus promotes the stabilization and activation of p53 wild type [15,86,87] , causing an increased expression of various p53 target genes [86] , including MDM2 itself [15,86,87] . The MDM2 gene contains a p53 DNA-binding site [84] , and the p53-MDM2 autoregulatory feedback loop encompasses p53-mediated upregulation of MDM2 gene transcription as well as MDM2-mediated downregulation of p53 expression and activity by targeting p53 to proteasomal downregulation [83][84][85] .…”

Section: Discussionmentioning

confidence: 99%

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

et al. 2016

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Background/Aims: The tumor suppressor p53 is depleted in many tumor cells by the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2) through MDM2/p53 interaction. A novel target for inhibiting p53 degradation and for causing reexpression of p53^{wild type} is inhibition of MDM2. The small molecule NVP-CGM097 is a novel MDM2 inhibitor. We investigated MDM2 inhibition as a target in neuroendocrine tumor cells in vitro. Methods: Human neuroendocrine tumor cell lines from the pancreas (BON1), lung (NCI-H727), and midgut (GOT1) were incubated with the MDM2 inhibitor NVP-CGM097 (Novartis) at concentrations from 4 to 2,500 nM. Results: While p53^{wild type} GOT1 cells were sensitive to NVP-CGM097, p53^mutated BON1 and p53^mutated NCI-H727 cells were resistant to NVP-CGM097. Incubation of GOT1 cells with NVP-CGM097 at 100, 500, and 2,500 nM for 96 h caused a significant decline in cell viability to 84.9 ± 9.2% (p < 0.05), 77.4 ± 6.6% (p < 0.01), and 47.7 ± 9.2% (p < 0.01). In a Western blot analysis of GOT1 cells, NVP-CGM097 caused a dose-dependent increase in the expression of p53 and p21 tumor suppressor proteins and a decrease in phospho-Rb and E2F1. Experiments of co-incubation of NVP-CGM097 with 5-fluorouracil, temozolomide, or everolimus each showed additive antiproliferative effects in GOT1 cells. NVP-CGM097 and 5-fluorouracil increased p53 and p21 expression in an additive manner. Conclusions: MDM2 inhibition seems a promising novel therapeutic target in neuroendocrine tumors harboring p53^{wild type}. Further investigations should examine the potential role of MDM2 inhibitors in neuroendocrine tumor treatment.

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Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

Cited by 155 publications

References 28 publications

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

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