RG7112

RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. [1]
P53 is a potent tumor suppressor that activates the transcription of a subset of genes controlling cell-cycle progression and apoptosis. MDM2 is a negative regulator of p53 that binds the transactivation domain of p53 and inhibits its ability to activate transcription. MDM2 is also an E3 ubiquitin ligase that targets p53 for proteosomal degradation. MDM2 overexpression is one of the mechanisms by which the wild type p53 function is impaired. [2]
RG7112 has been profiled extensively in many cell lines. In 15 cancer cell lines expressing wild-type p53, it shows IC50 in the range of 0.18 - 2.2 μM. However, the inhibition is much less in seven cancer cell lines with p53 mutation, IC50 5.7 - 20.3 μM. The overall selectivity is 14-fold.
In the animal models, RG7112-induced thrombocytopenia occurred rather late during the treatment period and persisted after drug discontinuation, suggesting that the drug acts on early hematopoietic progenitor cells. This is supported by the RG7112 ability to inhibit CFU-MK colonies formation by the CD34t cells in vitro. Administration of RG7112 in rats and monkeys reduces WBC counts and, to a lesser extent, hemoglobin levels. In patients treated with RG7112, neutropenia is among the serious adverse events while anemia occurred only in 2 of 20 patients. Interestingly, when tested in vitro, the same concentration of RG7112 that reduced CFU-MK colony formation do not significantly affect the formation of BFU-E and CFU-GM derived colonies.
References:
[1] Hernan Carol, C. Patrick Reynolds, Min H. Kang et al. Initial Testing of the MDM2 Inhibitor RG7112 by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2013;60:633–641
[2] Binh Vu, Peter Wovkulich, Giacomo Pizzolato et al. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development. ACS Med. Chem. Lett. 2013, 4, 466−469
[3] Camelia Iancu-Rubina, Goar Mosoyana, Kelli Glenn et al. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Experimental Hematology 2014;42:137–145

Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.[Pubmed:26459177]

Clin Cancer Res. 2016 Feb 15;22(4):868-76.

PURPOSE: RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted. EXPERIMENTAL DESIGN: Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A [relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia] and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. RESULTS: RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response. CONCLUSIONS: RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.

RG7112, a small-molecule inhibitor of MDM2, enhances trabectedin response in soft tissue sarcomas.[Pubmed:26288114]

Cancer Invest. 2015;33(9):440-50.

MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Selected sarcoma subtypes are being treated with Trabectedin in second line, which promotes DNA damage and p53-dependent apoptosis. The aim of this study was to evaluate the improvement of Trabectedin response with MDM2 inhibitors in soft tissue sarcomas. The antitumor effects of Trabectedin, Nutlin-3A and RG7112 as single agents or in combination were examined in vitro. RG7112 significantly synergized with Trabectedin in MDM2-amplified liposarcoma cells, representing a promising new therapeutic strategy for the treatment of sarcomas with MDM2 amplification.

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas.[Pubmed:26482041]

Clin Cancer Res. 2016 Mar 1;22(5):1185-96.

PURPOSE: p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. EXPERIMENTAL DESIGN: We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCL), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. RESULTS: MDM2-amplified PDCLs were 44 times more sensitive than TP53-mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 mumol/L vs. 21.9 mumol/L). MDM4-amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 mumol/L), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 mumol/L). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. CONCLUSIONS: These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2-amplified models suggests that additional markers of response to MDM2 inhibitors must be identified.

RG7112 is a potent, selective, first clinical, orally active and blood-brain barrier crossed MDM2-p53 inhibitor, with an IC50 of 18 nM and a KD of 11 nM for binding to MDM2.

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