RG-7112

RG-7112 is an inhibitor of mouse double-minute 2 protein (MDM2; IC₅₀ = 0.018 µM), an E3 ubiquitin ligase that ubiquitinates the tumor suppressor p53 and also acts as a negative regulator of p53 transcriptional activity.¹ RG-7112 binds to the p53 binding pocket of MDM2. It increases the levels of p53 and its transcriptional targets in SJSA-1 osteosarcoma cells.^1,2 It inhibits proliferation in cancer cell lines expressing wild-type p53 (IC₅₀s = 0.18-2.2 µM) and cell lines expressing mutant p53 (IC₅₀s = 5.7-20.3 µM). RG-7112 also prevents and reduces tumor growth in an SJSA-1 mouse xenograft model when administered at doses of 50 and 100 mg/kg per day, respectively.² However, it inhibits thrombopoiesis in vivo, decreasing platelet counts in rats when administered at doses of 50 and 100 mg/kg and in cynomolgus monkeys at doses of 10 and 20 mg/kg.³

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1. Vu, B., Wovkulich, P., Pizzolato, G., et al. Discovery of RG7112: A small-molecule MDM2 inhibitor in clinical development. ACS Med. Chem. Lett. 4(5), 466-469 (2013).

2. Tovar, C., Graves, B., Packman, K., et al. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res. 73(8), 2587-2597 (2013).

3. Iancu-Rubin, C., Mosoyan, G., Glenn, K., et al. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp. Hematol. 42(2), 137-145 (2014).