Biological Activity
amg-232 is a novel inhibitor of p53-mdm2 with ic50 value of 9.2 nm [1].tumor protein p53 (p53) is a very unstable protein with a half-life ranging from 5 to 30 min and participates in a variety of anticancer processes, such as inducing cell apoptosis and inhibiting angiogenesis. mouse double minute 2 homolog (mdm2), also named as e3 ubiquitin-protein ligase mdm2, involves in mediating p53 tumor suppressor. it has been conclusively demonstrated p53 is under-expressed in tumor cells [2].amg-232 is a potent p53-mdm2 interaction inhibitor and is regarded as a promising drug in clinic. when tested with sjsa-1 tumor cell line, amg-232 treatment resulted in cell-cycle arrest and inhibition of tumor cell proliferation via binding to mdm2 protein and robustly inducing p53 activity. it was shown that p53-mdm2 bond rang from a kd of 60 to 700 nm depending on the length of p53 peptide [3].in mouse model with sjsa-1 tumor cells subcutaneous xenograft, co-administration of amg-232 and chemotherapies induced dna damage and p53 activity which resulted in significantly superior antitumor efficacy and regression through arresting cell growth and inducting apoptosis [3].
References
[1]. rew, y., et al., discovery of am-7209, a potent and selective 4-amidobenzoic acid inhibitor of the mdm2-p53 interaction. j med chem, 2014. 57(24): p. 10499-511.
[2]. moll, u.m. and o. petrenko, the mdm2-p53 interaction. mol cancer res, 2003. 1(14): p. 1001-8.
[3]. canon, j., et al., the mdm2 inhibitor amg 232 demonstrates robust antitumor efficacy and potentiates the activity of p53-inducing cytotoxic agents. mol cancer ther, 2015. 14(3): p. 649-58.
