An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals

Abstract

BackgroundMI-319 is a synthetic small molecule designed to target the MDM2-P53 interaction. It is closely related to MDM2 antagonists MI-219 and Nutlin-3 in terms of the expected working mechanisms. The purpose of this study was to evaluate anti-lymphoma activity of MI-319 in WSU-FSCCL, a B-cell follicular lymphoma line. For comparison purpose, MI-319, MI-219 and Nutlin-3 were assessed side by side against FSCCL and three other B-cell hematological tumor cell lines in growth inhibition and gene expression profiling experiments.ResultsMI-319 was shown to bind to MDM2 protein with an affinity slightly higher than that of MI-219 and Nutlin-3. Nevertheless, cell growth inhibition and gene expression profiling experiments revealed that the three compounds have quite similar potency against the tumor cell lines tested in this study. In vitro, MI-319 exhibited the strongest anti-proliferation activity against FSCCL and four patient cells, which all have wild-type p53. Data obtained from Western blotting, cell cycle and apoptosis analysis experiments indicated that FSCCL exhibited strong cell cycle arrest and significant apoptotic cell death; cells with mutant p53 did not show significant apoptotic cell death with drug concentrations up to 10 μM, but displayed weaker and differential cell cycle responses. In our systemic mouse model for FSCCL, MI-319 was tolerated well by the animals, displayed effectiveness against FSCCL-lymphoma cells in blood, brain and bone marrow, and achieved significant therapeutic impact (p < 0.0001) by conferring the treatment group a > 28% (%ILS, 14.4 days) increase in median survival days.ConclusionOverall, MI-319 probably has an anti-lymphoma potency equal to that of MI-219 and Nutlin-3. It is a potent agent against FSCCL in vitro and in vivo and holds the promises to be developed further for the treatment of follicular lymphoma that retains wild-type p53.

The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents

“…Inhibition of the MDM2-p53 protein-protein interaction would block each of these mechanisms and is, therefore, an attractive target for restoration of p53 activity in tumor cells. Preclinical studies have indeed demonstrated restoration of p53 activity and inhibition of tumor growth by small-molecule MDM2 inhibitors (7)(8)(9)(10)(11). Previously, we reported the de novo design of AM-8553 as a potent and selective piperidinone inhibitor of the MDM2-p53 interaction (10).…”

Selective inhibitors of nuclear export for the treatment of non-Hodgkin's lymphomas

“…34 This led to our proposed hypothesis that p53 and its relative p73 could be a possible therapeutic target in NHL. Interestingly, most of the key TSP, including p53 and p73, carry a NES and are substrates for CRM1.…”

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

“…Oral administration of MI-319 at 300 mg/kg for 14 days resulted in significant tumor growth inhibition without any observed toxicity to the animals [97]. In a mouse model for follicular small cleaved cell lymphoma (FSCCL), MI-319 was tolerated well by the animals, displayed effectiveness against FSCCL cells in blood, brain, and bone marrow, and achieved significant therapeutic impact by conferring a greater than 28% increase in host life-span (by 14.4 days) in the treatment group [98]. Thus, MI-319 exhibited potent activity and was pursued for treatment against follicular lymphoma and pancreatic cancer that retain wild-type p53 both in vitro and in vivo.…”