Investigation of Small Molecule STAT3 Inhibitors

Abstract

STAT3 protein is crucial in cell proliferation, apoptosis, and host immune responses. In normal cell cycles STAT3’s activation is fleeting, but in many cancer cell lines aberrantly activated STAT3 promotes cancer progression. The inhibition of STAT3 protein’s ability to bind to DNA is an attractive treatment for aggressive carcinomas. The Tius Group has designed and synthesized a promising line of STAT3 inhibitors. The high activity of these inhibitors is attributable to the inclusion of a pentafluorobenzenesulfonamide or difluorocyanobenzesulfonamide moiety. A crucial fluorine atom in these inhibitors undergoes SNAr with a cysteine residue in the protein.In this thesis a small library of thirteen compounds and their SAR is reported. The difluorocyanobenzenesulfonamide “warhead” that was often included in inhibitors due to its potency, was found to be unstable in plasma due to reaction with native nucleophiles such as glutathione and plasma proteins. This provided the impetus to explore other scaffolds to attenuate the reactivity of the difluorocyanobenzenesulfonamide that would have desirable reactivity and pharmacokinetics. The SAR analysis of the “warhead” of the inhibitors is the focus of the work done. To attenuate the reactivity of the difluorocyanobenzenesulfonamide, inhibitors that incorporated constitutional isomers of the difluorocyanobenzesulfonamide: S3I-H265, S3I- H270, S3I-H275, and S3I-H289 were made. They indicated through their potency and lack of plasma stability that they would be unsuitable for further study. Inhibitors S3I-H254, S3I-H261 replaced the fluorines in the difluorocyanobenzenesulfonamide motif with a chlorine one at a time. Inhibitors S3I-H296, S3I-H299, and S3I-H308 were made in order to determine whether the substitution of an amide for the nitrile group would lead to higher potency and stability, however, the potency of these inhibitors was low. To explore whether alkyl substitution would improve the qualities of the pentafluorobenzenesulfonamide S3I-H287 was made. The activity of this compound was only slightly higher than that of S3I-H247 its parent. The activity of the inhibitors synthesized for this thesis indicate that novel reactive scaffolds need to be explored in order to provide a candidate for clinical trials.