Colorectal cancer is the 4th most common cancer globally and the 2nd most common cancer in Australia. Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been observed in over 50% of human colorectal carcinomas and its role in tumour progression has been confirmed in numerous mouse models. Previous data suggests that signalling through the Epidermal Growth Factor Receptor (EGFR) and the Interleukin (IL)-6 family of cytokines, contributes to STAT3 activation leading to continual tumourigenesis [1]. Importantly, we have recently shown that IL-11, a closely related IL-6 family member has a more prominent role than IL-6 during the progression of gastrointestinal cancers, including colorectal tumours [2]. In order to block STAT3 activity with the aim of overcoming STAT3-driven tumourigenicity, we evaluated a panel of 1167 FDA approved agents in their ability for inhibiting STAT3 activity. This was undertaken in human colorectal cancer cell lines using an adenoviral STAT3 luciferase reporter assay. We identified over 50 FDA approved agents (classified as “positive hits”) that were subsequently assessed in a secondary screen to evaluate which agents could inhibit IL-11, IL-6 and EGF mediated STAT3 phosphorylation by western blot analyses. Amongst these 19/50 positive agents in our secondary screen was Ponatinib (AP24534) a multi-targeted tyrosine kinase inhibitor, currently approved for the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib markedly reduced EGF, IL-6 and IL-11 mediated STAT3 phosphorylation and transcriptional activity (and gene expression of STAT3 regulated genes, including SOCS3). Ponatinib also reduced cell migration. Additionally, Ponatinib alone or in combination with other current anti-cancer agents used in colorectal cancer treatments (e.g. Cetuximab, 5FU, Oxaliplatin) reduced cell viability. Although our preliminary findings offer proof-of-principle evidence, the potential use of Ponatinib for treating STAT3 driven colorectal cancers requires further investigation.