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Dysfunction of the TP53 (p53) gene occurs in most if not all human malignancies. Two principal mechanisms are responsible for this dysfunction; mutation and downregulation of wild-type p53 mediated by MDM2/MDM4. Because of its almost universal inactivation in malignancy, p53 is a highly attractive target for the development of new anticancer drugs. Although multiple strategies have been investigated for targeting dysfunctional p53 for cancer treatment, only 2 of these have so far yielded compounds for testing in clinical trials. These strategies include the identification of compounds for reactivating the mutant form of p53 back to its wild-type form and compounds for inhibiting the interaction between wild-type p53 and MDM2/MDM4. Currently, multiple p53-MDM2/MDM4 antagonists are undergoing clinical trials, the most advanced being idasanutlin which is currently undergoing testing in a phase III clinical trial in patients with relapsed or refractory acute myeloid leukemia. Two mutant p53-reactivating compounds have progressed to clinical trials, i.e., APR-246 and COTI-2. Although promising data has emerged from the testing of both MDM2/MDM4 inhibitors and mutant p53 reactivating compounds in preclinical models, it is still unclear if these agents have clinical efficacy. However, should any of the compounds currently being evaluated in clinical trials be shown to have efficacy, it is likely to usher in a new era in cancer treatment, especially as p53 dysfunction is so prevalent in human cancers., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. TRIAL REGISTRATION: NCT01462175 (ClinicalTrials.gov), October 31, 2011., (© 2021. The Author(s).)

RG7388 (Idasanutlin) is a potent inhibitor of oncoprotein murine double minute 2 (MDM2). Herein we investigated the feasibility of developing 18 F-labeled RG7388 as a radiotracer for imaging MDM2 expression in tumors with positron emission tomography (PET). Two fluorinated analogues of RG7388, 6 and 7 , were synthesized by attaching a fluoronicotinyl moiety to RG7388 via a polyethylene glycol (PEG 3 ) or a propyl linker. The inhibitory potency (IC 50 ) of 6 and 7 against MDM2 was determined by a fluorescence polarization (FP)-based assay. Next, compound 6 was labeled with 18 F using a trimethylammonium triflate precursor to obtain [ 18 F]FN-PEG 3 -RG7388 ([ 18 F] 6 ), and its properties were evaluated in MDM2 expressing wild-type p53 tumor cell lines (SJSA-1 and HepG2) in vitro and in tumor xenografts in vivo. The FP assays revealed an IC 50 against MDM2 of 119 nM and 160 nM for 6 and 7 , respectively. 18 F-labeling of 6 was achieved in 50.3 ± 7.5% radiochemical yield. [ 18 F] 6 exhibited a high uptake (∼70% of input dose) and specificity in SJSA-1 and HepG2 cell lines. Saturation binding assays revealed a binding affinity ( K d ) of 128 nM for [ 18 F] 6 on SJSA-1 cells. In mice, [ 18 F] 6 showed fast clearance from blood with a maximum tumor uptake of 3.80 ± 0.85% injected dose per gram (ID/g) in HepG2 xenografts at 30 min postinjection (p.i.) and 1.32 ± 0.32% ID/g in SJSA-1 xenografts at 1 h p.i. Specificity of [ 18 F] 6 uptake in tumors was demonstrated by pretreatment of mice with SJSA-xenografts with a blocking dose of RG7388 (35 mg/kg body weight, i.p.). In vivo stability studies in mice using HPLC showed ∼60% and ∼30% intact [ 18 F] 6 remaining in plasma at 30 min and 1 h p.i., respectively, with the remaining activity attributed to polar peaks. Our results suggest that RG7388 is a promising molecular scaffold for 18 F-labeled probe development for MDM2. Additional labeling strategies and functionalizing locations on RG7388 are under development to improve binding affinity and in vivo stability of the 18 F-labeled compound to make it more amenable for PET imaging of MDM2 in vivo.

Patients with acute myeloid leukemia (AML) who achieve a morphologic complete remission still can have measurable residual disease (MRD) detected by multiparametric flow cytometry, molecular methods, or cytogenetics. Such patients with MRD have a high risk of disease recurrence over a short timeframe, but optimal treatment strategies are unknown. Outcomes with conventional treatment, including allogeneic hematopoietic cell transplantation, are worse than those for patients without MRD. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with MRD., (© 2019 American Cancer Society.)

The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53-regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers.

Purpose: MDM2 and CDK4 are frequently co-amplified in well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). We aimed to determine whether combined MDM2/CDK4 targeting is associated with higher antitumour activity than a single agent in preclinical models of DDLPS., Experimental Design: DDLPS cells were exposed to RG7388 (MDM2 antagonist) and palbociclib (CDK4 inhibitor), and apoptosis and signalling/survival pathway perturbations were monitored by flow cytometry and Western blotting. Xenograft mouse models were used to assess tumour growth and survival. Treatment efficacy was assessed by Western blotting, histopathology and tumour volume., Results: RG7388 and palbociclib together exerted a greater antitumour effect than either drug alone, with significant differences in cell viability after a 72-h treatment with RG7388 and/or palbociclib. The combination treatment significantly increased apoptosis compared to the single agents. We then analysed the in vivo antitumour activity of RG7388 and palbociclib in a xenograft model of DDLPS. The combination regimen reduced the tumour growth rate compared with a single agent alone and significantly increased the median progression-free survival., Conclusions: Our results provide a strong rationale for evaluating the therapeutic potential of CDK4 inhibitors as potentiators of MDM2 antagonists in DDLPS and justify clinical trials in this setting.

Background: The tumor suppressor p53 is frequently inactivated in non-small cell lung cancer (NSCLC). Activation of the p53 pathway by inhibition of its negative regulator MDM2 may offer an attractive approach for NSCLC therapy. We evaluated the antitumor activity of the small-molecule MDM2 inhibitor RG7388 in patient-derived xenograft (PDX) models of NSCLC., Methods: We investigated the effect of RG7388 treatment on cell proliferation, cell cycle arrest, and apoptosis using a panel of human NSCLC cell lines (A549, H157, H1650, H1395, and H358) and PDX cell lines (human lung cell lines 12, 137, 277, and 196). PDX-bearing mice were used to test the therapeutic efficacy and pharmacodynamic effects of RG7388 treatment., Results: We demonstrated that RG7388 promotes low nanomolar antiproliferative activity selectively in cell lines with wild-type p53 and p53 pathway activation, resulting in cell cycle arrest and apoptosis. In PDX models, oral administration of RG7388 led to potent dose-dependent and time-dependent activation of p53 and had a significant impact on p53 downstream targets. Daily treatment of RG7388 in mice at 50 and 80 mg/kg/day inhibited tumor growth in three wild-type p53 PDX models. Activation of the p53 pathway inhibited cell proliferation as observed by reduced Ki-67-positive cells in xenograft tumors. However, induction of apoptotic caspase activity was not observed in these tumors. Notably, RG7388 treatment remains effective in tumors lacking MDM2 amplification but expressing wild-type p53., Conclusions: MDM2 small-molecule inhibitor is effective in treating NSCLC tumors with wild-type p53, supporting further clinical investigation as a potential NSCLC therapy.

Potent and selective small-molecule inhibitors of the p53-MDM2 interaction intended for the treatment of p53 wild-type tumors have been designed and optimized in a number of chemical series. This review details recent disclosures of compounds in advanced optimization and features key series that have given rise to clinical trial candidates. The structure-activity relationships for inhibitor classes are discussed with reference to x-ray structures, and common structural features are identified.

Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.