Description

(±)-Nutlin-3 blocks the interaction of p53 with its negative regulator Mdm2 (IC₅₀ = 90 nM), inducing the expression of p53-regulated genes and blocking the growth of tumor xenografts in vivo.¹ CAY10682 is a pyrrolo[3,4c]pyrazole derivative that inhibits the p53-Mdm2 interaction as potently as (±)-nutlin-3 (K_i = 83 nM) and also dose-dependently reduces activation of the NF-κB pathway.² It specifically prevents phosphorylation of IκBα by the kinases IKKα, IKKβ, and IKK? (IC₅₀s = 80.5, 78.2, and 57.1 μM, respectively).² CAY10682 blocks the growth of cancer cells in vitro (IC₅₀s = 2-6 μM) and inhibits the growth of A549 cell xenografts in mice without significantly reducing body weight.²

Uses

p53-MDM2-IN-3 (Compound 5s) is an orally active p53-MDM2 inhibitor with a Ki value of 0.25 μM. p53-MDM2-IN-3 exerts antitumor activity by inhibiting NF-κB pathway[1].

in vivo

References

1. Vassilev, L.T., Vu, B.T., Graves, B., et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2 Science 303(5659),844-848(2004).
2. Zhuang, C., Miao, Z., Wu, Y., et al. Double-edged swords as cancer therapeutics: Novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-κB pathway J. Med. Chem. 57(3),567-577(2014).