An inhibitor of MDM2
SP 141 is a specific, potent and selective small-molecule antagonist of MDM2 with Ki value of 28±6 nM [2][3][4].
Mouse double minute 2 protein (Mdm2) is an ubiquitin ligase that promotes p53 degradation, a tumor suppressor that controls a major pathway protecting cells from malignant transformation [1].
SP 141 is a potent and selective MDM2 inhibitor. In breast cancer cell lines, SP-141 reduced cell viability with IC50 less than 1 μM (0.39-0.91 μM) and inhibited cancer cell colony formation in a concentration-dependent way. SP-141 also increased apoptosis and concentration-dependently inhibited cell proliferation. In both MCF-7 and MDA-MB-468 cells, SP-141 increased the degradation rate of the MDM2 protein [2].
In nude mice bearing MCF-7 and MDA-MB-468 xenograft tumours, intraperitoneal (i.p.) injection of SP-141 inhibited tumour growth by ~82% and ~80%, respectively [2]. In pancreatic xenograft and orthotopic mouse models, intraperitoneal (i.p.) injections of SP141 significantly inhibited the growth of pancreatic xenograft tumors and caused complete tumor regression of orthotopic pancreatic tumors [3]. In tumor-bearing nude mice, SP-141 had a short half-life in plasma and wide tissue distribution [4].
参考文献:
[1].? Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004 Feb 6;303(5659):844-8.
[2].? Wang W, Qin JJ, Voruganti S, et al. The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models. Nat Commun. 2014 Oct 1;5:5086.
[3].? Wang W, Qin JJ, Voruganti S, et al. Identification of a new class of MDM2 inhibitor that inhibits growth of orthotopic pancreatic tumors in mice. Gastroenterology. 2014 Oct;147(4):893-902.e2.
[4].? Nag S, Qin JJ, Voruganti S, et al. Development and validation of a rapid HPLC method for quantitation of SP-141, a novel pyrido[b]indole anticancer agent, and an initial pharmacokinetic study in mice. Biomed Chromatogr. 2015 May;29(5):654-63.
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