Novel STAT3 Inhibitors with Michael Acceptor from In-House Chemical Library as Therapeutics for Retinoblastoma

Abstract

Purpose : Our previous studies demonstrated that STAT3 inhibition could be a treatment option for retinoblastoma and chemicals with a Michael acceptor from our in-house library exerted inhibitory action on STAT3 activation. This study aims to develop potent STAT3 inhibitors from a library of 27 different derivatives with a Michael acceptor for the treatment of retinoblastoma.

Methods : To figure out cellular toxicity of 27 different chemicals with a Michael acceptor, SNUOT-Rb1 and Y79 cells from 2 different retinoblastoma cell lines were treated with STAT3 inhibitors. Cell viability was measured using WST-1 assay and the level of STAT3 phosphorylation was estimated by ELISA measurement. Quantitative real-time polymerase chain reaction was performed to measure the expression levels of target genes of STAT3 upon treatment with STAT3 inhibitors. From a library of 27 STAT3 inhibitors, the 2 most potent STAT3 inhibitors were selected. Then, in vivo therapeutic efficacy of them was investigated in the mouse orthotopic transplantation model. The toxicity of STAT3 inhibitors on normal cells and tissues was investigated at the levels of gene expression, cellular viability, and histologic integrity.

Results : Differential cellular toxicity, STAT3 phosphorylation, and expression of target genes were investigated in retinoblastoma cells upon treatment with 27 different chemicals with a Michael acceptor. The 2 most potent STAT3 inhibitors effectively inhibited the formation of tumors in the mouse orthotopic transplantation model. Interestingly, these STAT3 inhibitors did not significantly affect the cellular viability, the expression of genes regarding cell survival, and histologic integrity of the retina with a sufficient range of therapeutic window.

Conclusions : Novel STAT3 inhibitors identified from screening of an in-house library of chemicals with a Michael acceptor demonstrated potent in vitro and in vivo efficacy without definite toxicity on normal tissues. We expect that these STAT3 inhibitors can be utilized for the treatment of retinoblastoma.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.