MI-1061 is an Orally Active MDM2 Inhibitor
Posted On 2019-09-04
Inhibition of the MDM2-p53 protein-protein interaction is being actively pursued as a new anticancer therapeutic strategy. Our previous blogs have introduced typical MDM2 or MDM2-p53 inhibitors, including MI-773, RG7112, and AMG 232. Today, I would like to mention another MDM2 inhibitor MI-1061 came from a study from Aguilar A.
MI-1061 is a chemically stable, potent, and efficacious MDM2 inhibitor. MI-1061 is a potent and orally bioavailable MDM2 (MDM2-p53 interaction) inhibitor (IC50=4.4 nM; Ki=0.16 nM). Furthermore, MI-1061 potently activates p53, induces apoptosis, and has anti-tumor activity.
In vitro, MI-1061 achieves IC50=100 and 250 nM in the SJSA-1 and HCT-116 p53+/+ cell lines, respectively, and has IC50>10000 nM in the p53 knockout cell line HCT-116 p53–/–cell line.
In vivo, the authors evaluated MI-1061 for its ability to activate p53 in a PD experiment in the SJSA-1 tumor tissue harvested from mice. The animals treated with a single, oral dose of each compound at 100 mg/kg as indicated. As a result, MI-1061 effectively activated p53, leading to the accumulation of p53, MDM2, and p21 proteins. MI-1061 effectively induced robust cleavage of PARP in the tumor, indicative of strong apoptosis induction. Besides, consistent with the strong p53 activation and apoptosis induction in the tumor tissue, MI-1061 demonstrated strong antitumor activity and achieved significant tumor regression when administered orally daily for 14 days at 100 mg/kg. of note, all the mice treated with MI-1061 suffered no weight loss and did not show any signs of toxicity during or after the treatment.
Aguilar A, et al. Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannichring-opening-cyclization reaction mechanism in spiro-oxindoles. J Med Chem. 2014 Dec 26;57(24):10486-98.