– Brent Page – Laboratory of Chemical Biology and Drug Discovery – PhD project 11
State-of-the-art chemical biology techniques, such as the cellular thermal shift assay (CETSA), allow researchers to investigate direct interactions between experimental drugs and their biological targets with unprecedented accuracy. While these techniques have been primarily used to confirm target engagement for established drug molecules, these technologies can also be employed to identify novel chemical probes that facilitate the study of newly-discovered or “difficult-to-drug” biological targets. My group seeks to develop new target engagement assays and employ these techniques to identify small molecule inhibitors for targets that involved in the formation and progression of cancer. The STAT family of proteins are a particularly exciting focus for this work. STAT proteins are intimately involved in inflammation and tumorigenesis, but are difficult to target with small molecule inhibitors. ESR11 will work as part of a collaborative team to develop novel assays and small molecule probes that will be used to improve our understanding of the links between STAT signaling and cancer development.
Project 11 – Exploring the roles of STAT proteins in cancer development using targeted STAT inhibitors
Hypothesis: Developing novel methods for detecting interactions between STAT proteins and proposed inhibitors will allow for deconvolution of the STAT inhibitor landscape and further clarify the role of STAT proteins as inflammatory risk factors for cancer.
Background and Significance: Signal Transducer and Activator of Transcription (STAT) family proteins, especially STATs 1, 3 and 5 have been well-characterized with respect to their roles in cytokine signaling, inflammation and tumorigenesis[1]. This is especially prevalent within inflammatory conditions of the skin and in squamous cell carcinomas which have responded well to agents that block STAT signaling networks by targeting upstream kinases and receptors. While these types of ‘STAT signaling inhibitors’ continue to flood the scientific literature, the development of assays to determine if STAT inhibitors actually bind directly to STAT proteins are noticeably absent from the STAT signaling field[2]. Using a combination of modern chemical biology techniques, this project is focused on improving methodologies to characterize STAT inhibitors.
Objectives: This project aims to develop novel in vitro and in vivo methods to probe interactions between STAT proteins and inhibitors. These assays will be used to confirm or de-validate published STAT inhibitors by determining whether or not they actually bind to STAT proteins or whether they exert their effects via inhibition of other related (or unrelated) protein targets. In this project, the ESR will (1) optimize biophysical assays for detecting interactions between STATs and small molecule inhibitors; (2) assess mechanisms of action for known STAT inhibitors and identify novel targets within the STAT signaling pathway; (3) aid in the identification and optimization of novel STAT inhibitors; (4) explore the utility of STAT inhibitors in inflammation and cancer prevention.
Related readings
[1] Yu, H. et al. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9, 798-809 (2009).
[2] Furtek, S. L et al. Strategies and Approaches of Targeting STAT3 for Cancer Treatment. ACS Chem Biol 11, 308-318 (2016).