Therapeutic modulators of STAT signalling for human diseases

Abstract

The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials.

Figure 1. A schematic representation of the structures of the STAT proteins

Linear representations of the domain structures of the seven members of the signal transducer and activator of transcription (STAT) protein family: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. The transactivation domain contains a crucial tyrosine (Y) residue, the phosphorylation of which initiates STAT activation and dimerization between two monomers through a reciprocal phosopho-Tyr-SH2 domain interaction. The serine (S) residue present in the transactivation domain of certain STAT proteins is thought to enhance transcriptional activity when it is phosphorylated.

Figure 2. STAT signalling pathway, functions and associated diseases

Activation of signal transducer and activator of transcription (STAT) is promoted when a ligand (L) binds its receptor (R). The ligand–receptor interaction induces receptor phosphorylation (P), which recruits the STAT proteins to the phospho-motifs of the receptor. Phosphorylation of the critical tyrosine residue in the STAT protein is then initiated by tyrosine kinases, such as growth factor receptors, Janus kinases (JAKs) and SRC family kinases. Two phosphorylated STAT monomers dimerize through reciprocal pTyr-SH2 domain interactions, and the STAT–STAT dimers translocate to the nucleus where they bind to specific STAT-response elements in the target gene promoters and regulate transcription. The STAT-dependent induction of genes is essential for many physiological functions. The activation of normal STAT signalling is controlled by physiological negative modulators, such as suppressors of cytokine signalling (SOCS) and protein tyrosine phosphatases (PTPs), in accordance with normal cellular functions. Although the STAT proteins (STAT1 to STAT6) are differentially activated and promote varying cellular processes depending on the ligand and the context, collectively, their normal induction regulates cell growth, differentiation, survival and apoptosis. Their normal induction also regulates inflammatory and immune responses, embryonic development and mammary gland development. By contrast, defective or abnormal STAT signalling is associated with various human diseases, including susceptibility to infection, immune disorders, many types of cancer, asthma and allergic diseases. IFN, interferon; IL-2Rα, interleukin-2 receptor-α; T_H, T helper.

Figure 3. Models of inhibition of STAT signalling

a | Small-molecule dimerization disruptors (SMDDs) or phospho-peptidomimetic inhibitors (PPMIs) target the phospho-Tyr-SH2 domain interaction at the interface of dimers of signal transducer and activator of transcription (STAT) proteins. This leads to the disruption of STAT–STAT dimers and the formation of STAT–SMDD or STAT–PPMI heterocomplexes, leading to a suppression of STAT signalling and function. b | The binding of ligands, such as growth factors and cytokines, to their cognate receptors on the cell surface induces STAT tyrosine phosphorylation and activation, and this process is competitively inhibited by antibody-based therapeutics. Tyrosine kinases that mediate STAT phosphorylation, leading to STAT–STAT dimer formation, are the targets of small-molecule tyrosine kinase inhibitors. The overall effect of these modulators is to block the induction of STAT phosphorylation and signalling. c | Decoy oligdeoxyonucleotides (ODNs) compete against the DNA-response elements in the target gene promoters for the binding of the active STAT–STAT dimers. The interaction of ODNs with STAT–STAT dimers precludes the binding of the dimers to target gene promoters, thereby preventing the induction of STAT-responsive genes. d | The induction of protein tyrosine phosphatases has been noted to occur in response to certain STAT inhibitors, including sorafenib analogues and natural products. This promotes the dephosphorylation of the phospho-STAT proteins leading to the suppression of their signalling and function.