Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097

Abstract

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.

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^{wild type} Neuroendocrine Tumor Cell Line GOT1

“…The seemingly paradoxical increment in MDM2 and pMDM2 expression following the administration of the MDM2 inhibitor NVP-CGM097 is explained by the p53-MDM2 autoregulatory feedback loop, as reported by others [15,[83][84][85][86][87] . 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] .…”

“…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] .…”

The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice

“…Small molecule inhibitors that disrupt the MDM2-p53 interaction have proven effective in a subset of tumor models and patient tumors with wild-type p53 (Andreeff et al, 2015; Jeay et al, 2015; Lv et al, 2015; Weisberg et al, 2015). In contrast, tumors with pathogenic TP53 mutations or biallelic deletions are typically resistant to MDM2 inhibition.…”

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

“…The assay was conducted as recommended by Meso Scale Discovery with the exception that protein lysate was incubated overnight. The development of the patient-derived AML xenograft model in mice and study design has been previously described 29 . An additional group of mice (n = 7) was added to the study on day 35 after tumour implantation and treated with SHP099 (75 mg per kg daily) for 34 days.…”