MSc by Research: Targeting ‘Undruggable’ Oncoproteins via Induced Proximity

About the Project

Many well-established cancer drivers, such as K-Ras and β-catenin, have long been considered ‘undruggable’, as traditional drug development approaches have failed to effectively inhibit their activity. Tackling these elusive targets requires innovative strategies that go beyond conventional drug design.

One promising approach lies in the manipulation of protein post-translational modifications (PTMs) that regulate protein function in cells by modulating their activity, stability, localization, and interactions. In fact, dysregulation of PTMs, often due to mutations in enzymes or their substrate proteins, is a hallmark of many cancers.

The MRes project, which will be based in the Sapkota Lab at the MRC Protein Phosphorylation and Ubiquitylation Unit, will explore how induced proximity, i.e. by bringing enzymes into proximity with oncoproteins, can be used to modulate PTMs on oncoproteins and potentially inhibit their cancer-driving functions. The Sapkota lab has pioneered several powerful induced-proximity platforms, including the AdPROM (Affinity-directed PROtein Missile) and the BDPIC (bromoTAG-dTAG Proximity-Inducing Chimera) systems. These platforms enable the targeted addition or removal of PTMs, such as ubiquitylation, phosphorylation, and dephosphorylation, leading to outcomes like protein degradation, inactivation or mis-localization. Building on these cutting-edge tools, the student will investigate their utility in targeted catalysis of these and other PTMs (e.g. reversible glycosylation, acetylation, methylation), the resulting effects on oncoprotein function, consequences for cancer cell proliferation and survival.

The student will receive world-class training in state-of-the-art techniques in molecular and cell biology, including CRISPR/Cas9 genome editing, biochemistry, microscopy, and proteomics. The student will be embedded in a highly collaborative, diverse and well-resourced research environment, with an opportunity to contribute to cutting-edge therapeutic strategies targeting intractable cancer proteins.

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.