LQZ-7I is an Orally Active Survivin-Targeting Inhibitor
Posted On 2020-07-11
Survivin is a member of the inhibitor of apoptosis (IAP) protein family that inhibits caspases and blocks cell death. Caspases highly expressed in most cancers and are associate with a poor clinical outcome. The differential expression of survivin in cancer cells compared to normal tissues and its role as a nodal protein in a number of cellular pathways make it a high target for different therapeutics. LQZ-7I is a surviving-targeting inhibitor.
LQZ-7I has improved cytotoxicity with an IC50 of 3.1 μM against C4-2 cells and 4.8 μM against PC-3 cells compared with the parent compound LQZ-7, which has IC50 values of 9.1 and 8.1 μM, respectively. In particular, it significantly decreases the SEAP reporter expression and inhibits cell survival via inhibiting survivin dimerization. Moreover, LQZ-7I induces survivin degradation in a proteasome-dependent manner and induces apoptosis. LQZ-7I treatments reduce the half-life of survivin from 2.2 and 2.3 h to 50 and 25 min in C4-2 and PC-3 cells, respectively. Thus, LQZ-7I induces survivin degradation in both cell lines.
LQZ-7I orally and effectively inhibits xenograft tumor growth and induces survivin loss in tumors. Furthermore, it inhibits the growth of PC-3 xenograft tumors by inhibiting surviving. Treatment of the compound (100 mg/kg) significantly suppresses tumor growth without any notable adverse effect on the mice as indicated by lacking changes in body weight. LQZ-7I is also selective to survivin and induces apoptosis and survivin degradation in a proteasome-dependent manner. As a result, LQZ-7I inhibits cancer cell survival and suppresses xenograft tumor growth.
All in all, Survivin is a homodimeric member of the IAP family. LQZ-7I significantly inhibits survivin dimerization.
Robert Peery, et al. Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation. J Med Chem. 2020 Jun 9.