Development of Small Molecule degraders of ILK for glioblastoma therapy

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Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumour in adults, which is essentially incurable with median survival of about 12-18 months from diagnosis. There is an urgent need to identify and validate new molecular targets that reveal common biological vulnerabilities across GBM sub-types, and to devise novel therapeutic strategies. Integrin-linked kinase (ILK), an enigmatic pseudo-kinase downstream of integrins, drives the malignant GBM and acts as a potentially valuable target. Although undruggable ILK lacks catalytic activity, Prof Unciti-Broceta and Prof Frame have identified a novel chemical strategy to disrupt ILK activity by targeting its pseudo-kinase (ATP binding) site, which leads to protein degradation. Inspired in the strong preliminary data, I have devised a strategy based largely on promoting degradation of the ILK-Pinch-Parvin (IPP) complex by blocking the binding of these key interacting partners via small molecule structural disruptors. Based on an identified hit scaffold, I will combine both ligand and structure-based (in silico) drug design, focused chemical library synthesis and phenotypic screening in an iterative manner, with the goal to bias chemical discovery towards drug-like compounds that elicit IPP complex degradation and antiproliferative activities in GBM stem cells. After several iterations of design, synthesis and phenotypic screening, promising compounds will be carried out advanced phenotypic screening and DMPK studies to generate best candidate/s. Finally, I will explore the mode of action of best inhibitor/s by co-crystallization and evaluate in vivo anticancer efficacy of best inhibitor/s in GBM xenograft models. Through the discovery of novel small molecule ILK degraders, my ambitious project aims to provide a new paradigm and strategy for the treatment of GBM.