RG7388

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Background

RG7388 is a second generation clinical MDM2 inhibitor with superior potency and selectivity. It is a highly potent pyrrolidine compound. RG7388 is more potent and selective than RG7112. In human cancer cell lines, IC50 value of RG7388 in HTRF binding assays is 6 nM and IC50 value of RG7388 in MTT proliferation assays is 0.03μM. [1]In human cancer cell lines, RG7388 blocks p53−MDM2 binding and effectively activates the p53 pathway, leading to cell cycle arrest and/or apoptosis in cell lines expressing wild-type p53 and tumor growth inhibition or regression of osteosarcoma xenografts in nude mice. RG7388 is undergoing clinical investigation in solid and hematological tumors. [1]In rhabdomyosarcoma xenografts mice, RG7388 increased the activity of Ionizing radiation (XRT) in both rhabdomyosarcoma models and did not increasing local XRT-induced skin toxicity. Changes in TP53-responsive genes were consistent with the synergistic activity of RG7388 and XRT in the Rh18 model. [2]RG7388 GI50 concentrations of wt p53 was a >200-fold difference versus mutant cell lines. Comparing with MYCN- cells, Tet21N MYCN+ cells were more sensitive to RG7388. In five p53-wt neuroblastoma cell lines, combining use of RG7388 with cisplatin, topotecan, doxorubicin, busulfan and temozolomide were synergistic led to increased apoptosis and higher caspase-3/7 activity. RG7388 is highly potent against p53-wt neuroblastoma cells, and strongly supports its further evaluation as a novel therapy for patients with high-risk neuroblastoma and wt p53 to potentially improve survival and/or reduce toxicity. [3]

1.Ding Q, Zhang Z, Liu JJ et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013 Jul 25;56(14):5979-83.
2.Phelps D, Bondra K, Seum S et al. Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma. Pediatr Blood Cancer. 2015 Apr 1. doi: 10.1002/pbc.25465.
3.Chen L, Rousseau RF, Middleton SA et al. Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget. 2015 Apr 30;6(12):10207-21.