Old Road Campus Research Building
Secreted growth hormones and cytokines regulate the key physiological processes of growth and differentiation as well as responses to injury and infection. They include some notable therapies such as growth hormone (GH), insulin and interferons. However, inappropriate growth signals can drive human cancer while excessive cytokine (interferon and interleukin) responses underlie autoimmune and inflammatory diseases such as rheumatoid arthritis, diabetes and asthma.
My group is interested in how these signals are regulated inside the cell by phosphorylation and uses the tools of structural biology. Classically, the receptor (RTK) and non-receptor (PTK) protein tyrosine kinases create docking sites for the recruitment of SH2 effector proteins (e.g. GRB2, STATs) regulated by the action of phosphatases (PTPs). Similarly, TGF-ß/BMP receptor serine kinases (RSK) recruit SMAD MH2 domains for the control of embryogenesis and stem cell development. More recently phosphorylation has been recognized as a control switch for protein degradation by E3 ubiquitin ligases.
As part of the structural genomics consortium (SGC) we are targeting the kinase receptors and their interaction with E3 ligases, with particular interest in their relevance for human disease. We recently solved several crystal structures of the TGF-ß/BMP receptor family which is under investigation in clinical trials for tumour angiogenesis, muscular dystrophy and multiple myeloma. Together with the group of Prof. Stefan Knapp we have also dentified anti-leukemic inhibitors of the PIM1 survival kinase that is known to be essential for v-Abl transformation. Recent work has focussed on the BTB-Kelch family of E3 ubiquitin ligases which are linked to the development of certain cancers, development and neurodegeneration.
Sequence and structural variations determining the recruitment of WNK kinases to the KLHL3 E3 ligase
Chen Z. et al, (2020)
Receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold.
Suebsuwong C. et al, (2020), European journal of medicinal chemistry, 200
Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.
Ensan D. et al, (2020), Journal of medicinal chemistry, 63, 4978 - 4996
A Highly Selective Chemical Probe for Activin Receptor-like Kinases ALK4 and ALK5
Hanke T. et al, (2020), ACS Chemical Biology
Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas
Fortin J. et al, (2020), Cancer Cell