Direct Targeting Options for STAT3 and STAT5 in Cancer

Abstract

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.

Keywords: STAT3; STAT5; cancer; small-molecule inhibitors.

Figure 1

Functions of STAT5. (a) Domain structure of STAT5. Position of the critical activating tyrosine phosphorylation site is depicted with Y. ND—N-domain; CCD—coiled-coil domain; DBD—DNA-binding domain; L—linker; SH2—SH2 domain; TAD—transactivation domain. (b) Conformational changes of STAT5 from an unphosphorylated antiparallel dimer (uSTAT5) to a phosphorylated parallel dimer (pYSTAT5). (c) Dimer and oligomer conformations of STAT5 result in binding to GAS sites on DNA with different affinities, resulting in expression of different genes. Examples of dimer versus tetramer target genes are incorporated from [32,33].

Figure 2

Role of STAT3/5 in regulating the chromatin landscape. (a) pYSTAT3 interacts with and recruits chromatin remodelers, and thereby promotes changes in chromatin compaction. (b) uSTAT5 and pYSTAT5 interact with different chromatin remodelers, thereby promoting chromatin changes associated with euchromatin (green arrows) or heterochromatin (red arrows) formation.

Figure 3

Chemical structures of STAT3 and STAT5 inhibitors (in their order of citation in the main text). Compounds with identical names (Cpd1) are further specified by citations.