[(4R,5S)-4,5-Bis(4-chlorophenyl)-2-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihydro-4,5-dimethyl-1H-imidazol-1-yl][4-[3-(methylsulfonyl)propyl]-1-piperazinyl]methanone

Description

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. 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. 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. 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.

Uses

RG 7112 is MDM2 antagonist. It can be used in biological study of single mouse analysis on evaluation of alternative in vivo drug screening methodology.

in vivo

target

MDM2

References

[1] BINH VU*. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development[J]. ACS Medicinal Chemistry Letters, 2013, 4 5: 466-469. DOI: 10.1021/ml4000657
[2] CHRISTIAN TOVAR. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models.[J]. Cancer research, 2013, 73 8: 2587-2597. DOI: 10.1158/0008-5472.can-12-2807
[3] CAMELIA IANCU-RUBIN . Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis[J]. Experimental hematology, 2014, 42 2: Pages 137-145.e5. DOI: 10.1016/j.exphem.2013.11.012