“…NVP-CGM097 and NVP-CFC218 are substituted 1,2-dihydroisoquinolinone derivatives that were designed to mimic three key hydrophobic interactions made by p53 residues Phe19, Trp23, and Leu26 in the HDM2 pocket (Kussie et al, 1996; García-Echeverría et al, 2000; Furet et al, 2012) (Figure 1A). The dihydroisoquinolinone core occupies the center of the cleft and allows for the positioning of appropriate substituents in this sub-pocket (manuscript in preparation).10.7554/eLife.06498.003Figure 1. TP53 wild-type status is necessary but not sufficient to predict sensitivity to NVP-CGM097 and NVP-CFC218.( A ) Chemical structure of NVP-CGM097 and NVP-CFC218.…”
Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53–HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53–HDM2 inhibitors, such as NVP-CGM097.DOI:
http://dx.doi.org/10.7554/eLife.06498.001
“…NVP-CGM097 and NVP-CFC218 are substituted 1,2-dihydroisoquinolinone derivatives that were designed to mimic three key hydrophobic interactions made by p53 residues Phe19, Trp23, and Leu26 in the HDM2 pocket (Kussie et al, 1996; García-Echeverría et al, 2000; Furet et al, 2012) (Figure 1A). The dihydroisoquinolinone core occupies the center of the cleft and allows for the positioning of appropriate substituents in this sub-pocket (manuscript in preparation).10.7554/eLife.06498.003Figure 1. TP53 wild-type status is necessary but not sufficient to predict sensitivity to NVP-CGM097 and NVP-CFC218.( A ) Chemical structure of NVP-CGM097 and NVP-CFC218.…”
Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53–HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53–HDM2 inhibitors, such as NVP-CGM097.DOI:
http://dx.doi.org/10.7554/eLife.06498.001
“…Several potent MDM2 binders based on these scaffolds and cocrystallized with the MDM2 receptor have been described by us and others in the past. 3,6,7,23 A high-ranking β-lactam compound after energy minimization is shown in Fig. 1E.…”
Using the pharmacophore-based virtual screening platform ANCHOR.QUERY, we morphed our recently described Ugi-4CR scaffold towards a β-lactam scaffold with potent p53-MDM2 antagonizing activities. 2D-HSQC and FP measurements confirm potent MDM2 binding. Molecular modeling studies are used to understand the observed SAR in the β-lactam series.
“…Briefly, a screen of 50,000 compounds exploiting a three hotspot 2D/3D pharmacophore led to identification of a series of isoquinolinones, the subsequent optimization of which revealed a novel binding mode with changes in protein organization associated with His 96 interactions (38). Additional changes resulted in the clinical candidate CGM097, a substituted 1,2-dihydroisoquinolinone derivative designed to mimic three key hydrophobic interactions made by p53 residues with Phe19, Trp23 and Leu26 in the HDM2 pocket (8, 39). CGM097 (structure revealed in 38, 40) binds to the p53 pocket of HDM2 with high potency and exceptional selectivity; in biochemical assays, CGM097 displaces the p53 peptide from the surface of HDM2 with an IC 50 of 1.7 nM, compared with an IC 50 of 2,000 nM for HDMX (38, 40).…”
The tumor suppressor, p53, is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing wild-type (wt) p53, the HDM2 protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell cycle arrest. Here, we investigated the ability of the novel HDM2 inhibitor, CGM097, to potently and selectively kill wt p53-expressing AML cells. The anti-leukemic effects of CGM097 were studied using cell-based proliferation assays (human AML cell lines, primary AML patient cells and normal bone marrow samples), apoptosis and cell cycle assays, ELISA, immunoblotting, and an AML patient-derived in vivo mouse model. CGM097 potently and selectively inhibited the proliferation of human AML cell lines and the majority of primary AML cells expressing wt p53, but not mutant p53, in a target-specific manner. Several patient samples that harbored mutant p53 were comparatively unresponsive to CGM097. Synergy was observed when CGM097 was combined with FLT3 inhibition against oncogenic FLT3-expressing cells cultured both in the absence as well as the presence of cytoprotective stromal-secreted cytokines, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. These data suggest that CGM097 is a promising treatment for AML characterized as harboring wt p53 as a single agent, as well as in combination with other therapies targeting oncogene-activated pathways that drive AML.
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