Zaman, Niyaz; (2025) Design and Validation of Autophagy Targeting Chimeras. Doctoral thesis (Ph.D), UCL (University College London).

Text Niyaz Zaman - PhD Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 May 2026. Download (27MB)

Abstract

Targeted protein degradation (TPD) has opened new opportunities to investigating signalling pathways as a research tool, and as a unique therapeutic strategy using heterobifunctional chimeric small molecules to drug previously undruggable proteins. New, emerging strategies using the autophagy-lysosome system, termed AUtophagy TArgeting Chimeras (AUTACs) expand on the degrader arsenal and repertoire of targets that can be degraded. Autophagy is an evolutionarily conserved recycling process observed in all known eukaryotes. It is a complex process, used to degrade intracellular cargoes such as soluble proteins and insoluble protein aggregates, non-protein molecules and organelles back to fundamental molecules. The aim of this thesis was to develop small molecules to exploit this process to enable degradation of targets of interest. Current AUTACs use preformed double membrane structures termed autophagosomes and tether a target of interest (TOI) to an autophagosome cargo protein via a chimeric small molecule. In this thesis, I developed AUTACs based on the de novo biogenesis of autophagosomes at the target site by linking a small molecule activator for the autophagy initiating kinase, ULK1 to a TOI ligand (ergo, ULK1-TArgeting Chimera [ULKTAC]). I demonstrate local recruitment of ULK1 is sufficient to induce the formation of an autophagosome at the site of recruitment, and, I confirm the ULK1 dependency and lysosomal requirement for activity – highlighting proteasomal independence. Using a mitochondrion targeting ligand, I show ULKTAC activity at mitochondria induces mitophagy, and, using Parkinson’s disease patient-derived fibroblasts, show that this acts independently of canonical mitophagy signalling. Additionally, I discover how ULKTACs can be designed to degrade nuclear targets, such as the transcriptional co-activator, BRD4, and the transcription factor c-MYC, known to be dysregulated in ~70% of human cancers. Hence, this thesis culminated in the development of a novel biogenic autophagy-based degrader system, with potential to have widespread impact and be transformative to biomedical research.

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