Molecular characterization of a novel class of STAT3 inhibitors
Research area: Biologia Strutturale Computazionale
Associate members: Andrea Cavalli
- Jacopo Sgrignani, Scientist
Status: In progress
Transcription factors (TFs) are central nodes in multiple oncogenic signalling pathways and represent attractive targets for development of novel cancer treatment strategies. However, very few direct pharmacological inhibitors of transcription factors are currently in the clinical trials. Signal Transducer and Activator of Transcription 3 (STAT3) belongs to the STAT family of transcription factors. As other STAT members, STAT3 is a cytoplasmic protein and is regulated by multiple post-transcriptional modifications (PTM), like phosphorylation, methylation and acetylation.
Increased expression and activity of STAT3 is very common in human cancers. STAT3 has a central role in critical signalling pathways for tumour initiation and progression. STAT3 drives tumour progression by promoting proliferation, survival, metabolic adaptation, tumour angiogenesis and immune tolerance and its downregulation by genetic or pharmacological means prevents or reverts tumorigenesis.
Many anticancer drugs inhibit upstream signaling pathways (e.g., JAK, EGFR) and affect STAT3 activation. In addition to these “indirect” inhibitors of the STAT3 pathway (e.g., JAK inhibitors), there is increasing interest in developing “direct” inhibitors of STAT3 that might interfere with the multiple diverse functions of this TF.
A number of small molecule compounds as well as natural products have been identified as direct STAT3 inhibitors (STAT3i). The aim of this study is to investigate the mechanism of action of a novel class of compounds with STAT3 inhibitory activity. In particular, we will study two compounds that interfere effectively with STAT3 and have potent anticancer activity in various tumor models. Experimental results suggest, that this new class of compounds acts by promoting the formation of large aggregates of STAT3 and that the formation of this aggregates is a direct consequence of conformational changes, disruption of specific inter-domain interactions and partial unfolding of STAT3 induced by STAT3i.
The objective of this study is the characterization of the mechanism of action of STAT3i at a molecular level. In particular we aim to:
- Investigate the effect of small molecule drug binding on the stability of inter-domain interactions and the mobility of STAT3 domains.
- Investigate the effect of changes in stability and mobility of STAT3 domains on the formation of aggregates and its role in STAT3 inactivation.