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Abstract The incidence and death rates for pancreatic adenocarcinoma in the US have been increasing by about 1% per year and the death rate has increased by approximately 0. 2% yearly. The five-year survival rate has remained below 10% for many years. With surgery, radiation, and chemotherapy being the main treatment options to extend survival or for symptom relief, there is an urgent unmet need for effective new treatment options. Signal Transducer and Activator of Transcription (Stat) 3, one of the Stat family members, is aberrantly activated in human pancreatic and many other cancers. Aberrantly-active Stat3 promotes abnormal tumor-cell intrinsic and extrinsic mechanisms, including dysregulation of gene expression and mitochondria energy metabolism in the tumor cells, and suppression of immune cell functions in the tumor microenvironment. Stat3 is therefore an important target for therapeutic development. Herein we present two small molecules, H182 and H333, which are covalent inhibitors of Stat3 and that potently block Stat3 DNA-binding activity in vitro, with IC50 0. 66-0. 98 µM. H182 and its structural analog, H333 bind Stat3 via irreversible covalent interactions with key cysteine residues in the Stat3 DNA-binding domain to induce a time-dependent inhibition of Stat3 activity. Both compounds inhibit intracellular constitutive Stat3 tyrosine phosphorylation and induce loss of viable cells and apoptosis in vitro of human pancreatic Panc-1 and Mia-Paca2 cells. H333 is 13-fold more specific and H182 is 4-fold more specific against tumor cells over normal cells. Furthermore, MiaPaca-2 cells treated with H182 and analyzed by Seahorse showed dramatically decreased mitochondria respiration. Notably, xenograft models of MiaPaca2 treated with H182 or H333 via i. p. every other day for 27 days showed dramatic growth inhibition. Collectively, our results identify H182 and H333 as therapeutically-viable small molecules with unique irreversible mechanism of Stat3 inhibition which accounts for their strong antitumor effects against human pancreatic tumor xenografts. Citation Format: Yue Chen, Ning Zhai, Peibin Yue, Christine Brotherton-Pleiss, Wenzhen Fu, Kayo Nakamura, Weiliang Chen, Marcus Tius, Francisco Lopez-Tapia, James Turkson. Irreversible covalent azetidine-based small molecule inhibitors of Stat3 activity block growth of human pancreatic tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 663.
Chen et al. (Fri,) studied this question.