Abstract B137: Novel potent salicylic, benzoic, and benzohydroxamic acid-based small-molecule STAT3 inhibitors induce antitumor effects in breast cancer xenografts

Abstract

Abstract We investigated the molecular determinants for the activity of the previously reported salicylic BP-1-102 (IC50 6.8 ± 2.5 μM), benzoic SH4-54 (IC50 4.4 ± 0.3 μM), and benzohydroxamic acid SH5-07 (IC50 3.9 ± 0.6 μM) small-molecule STAT3 inhibitors in order to derive structurally optimum analogs with improved potency and pharmacokinetic parameters. All three leads are based on N-methylglycinamide scaffold, with its two amine groups condensed with three different functionalities. The three functionalities were separately modified to generate various series of new analogs. The inhibitory activities of the new analogs against STAT3 DNA-binding in vitro were determined by electrophoretic motility shift assay. Some new analogs show dramatically improved potency compared to the corresponding lead compounds. Notably, analogs H098, H127, H142, H145, H152, and H155 showed more than 10-fold improved potency in inhibiting STAT3 DNA-binding activity in vitro, with IC50 of 300 - 600 nM. Using analogs H105 and H120, we show that the new analogs decreased STAT3 DNA-binding activity and phosphorylation at Tyr705 in MDA-MB-231 and MDA-MB-468 cells, two human triple-negative breast cancer lines harboring constitutively active STAT3, within as early as 30 min. Furthermore, the new analogs potently inhibited the growth and viability of the human cancer cells with persistently active STAT3, with IC50 of 1.2 - 2.0 µM. The potent analogs specifically disrupted STAT3 DNA-binding activity in vitro over that of STAT1 and STAT5, and they further showed minimum inhibitory effect on the proliferation of human cancer cells that do not harbor persistently active STAT3. Initial in vivo efficacy study in nude mouse model showed that oral administration of H105 and H120 suppressed the growth of tumor xenografts generated from human breast cancer line harboring constitutively active STAT3. Thus, we have made substantial progress and broken the nanomolar barrier in developing STAT3 inhibitors, and these compounds are the first nanomolar STAT3 inhibitors reported to date that are direct disruptors of STAT3 activation, which show in vivo activity. Citation Format: Peibin Yue, Francisco Lopez-Tapia, Christine Brotherton-Pleiss, Marcus Tius, James Turkson. Novel potent salicylic, benzoic, and benzohydroxamic acid-based small-molecule STAT3 inhibitors induce antitumor effects in breast cancer xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B137.