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Cancers (Basel). 2019 Dec 3;11(12). pii: E1930. doi: 10.3390/cancers11121930.

Direct Targeting Options for STAT3 and STAT5 in Cancer.

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Institute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, Austria.
Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada.
Centre for Medicinal Chemistry, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada.
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, H-1117 Budapest, Hungary.
Department I of Internal Medicine, Center for Integrated Oncology (CIO), Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), and Center for Molecular Medicine Cologne (CMMC), Cologne University, 50937 Cologne, Germany.


Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is associated with T-cell prolymphocytic leukemia, T-cell acute lymphoblastic leukemia and γδ T-cell-derived lymphomas. Hyperactive STAT3 and STAT5 are also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. Classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. However, the functions of STAT proteins are not limited to their phosphorylated dimerization form. In this review, we discuss the functions and the roles of unphosphorylated STAT3/5 in the context of chromatin remodeling, as well as the impact of STAT5 oligomerization on differential gene expression in hematopoietic neoplasms. The central involvement of STAT3/5 in cancer has made these molecules attractive targets for small-molecule drug development, but currently there are no direct STAT3/5 inhibitors of clinical grade available. We summarize the development of inhibitors against the SH2 domains of STAT3/5 and discuss their applicability as cancer therapeutics.


STAT3; STAT5; cancer; small-molecule inhibitors

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