AutoCure: an Autophagy- clinical platform for undruggable targets.

Approximately 74% of proteins in the human proteome are not targeted by any known drugs. With a BBSRC funded LIDo PhD studentship we have produced a new technology platform that degrades and removes cellular targets by initiating the natural autophagy process at the site of the target. We term our novel degradation technology platform, AUTOCURE. A key advantage of this platform is the ability to produce clinically relevant degradation of conventionally undruggable targets, such as the cancer super-controller MYC and faulty mitochondria. This proposal aims to develop this technology into a commercial platform for wide use across many targets and indications. Our inability to drug many promising therapeutic targets prevents us from turning key molecular insights into effective healthcare interventions. PROteolysis TArgeting Chimeras (PROTACs) and molecular glues are new exciting degradation technologies which utilise the cells’ 26S proteasome to degrade target proteins. However, PROTACs and molecular glues are mostly limited to the degradation of small soluble proteins. Autophagy: a universally conserved cellular recycling mechanism, is required for the degradation of damaged or long-lived proteins, cytoplasmic contents, and organelles like mitochondria - a significantly wider substrate profile versus the 26S proteasome. We have generated bi-functional molecules to co-localise the autophagy initiator kinase ULK1 with our target of interest, enabling degradation by the de novo creation of an autophagosome around the target. We termed these molecules ULK1-TArgeting Chimeras (ULKTACs) . Our data shows AUTOCURE is non-toxic, does not disrupt cell homeostasis, and leaves, for example healthy mitochondria untouched. AUTOCURE does not use existing autophagosomes for targeted degradation, but uniquely initiates autophagosomes at the targeted site. This represents a significant advance over existing autophagy-based technologies . Our technology also degrades multiple target types as shown by our strong proof of concept data. We have directly targeted the previously undruggable transcription factor MYC, which is amplified and aberrantly expressed in >70% of cancers. MYC is intrinsically disordered, lacking well-defined pockets for traditional drugs. Using our AUTOCURE platform we repurposed a weak (10 micromolar) c-MYC inhibitor into an ULKTAC to enable the direct autophagy-mediated degradation of the c-MYC/MAX complex at nanomolar concentrations. This impaired c-MYC controlled gene expression, rescued oncogenic c-MYC induced replication stress and importantly specifically kills MYC-addicted cancer cells . A second undruggable target are damaged mitochondria: in cells from patients with Parkinson’s disease, we showed effective clearance of damaged or fragmented mitochondria. Studies on cells from people with ALS (motor neurone disease) are ongoing. Together these examples illustrate the power of this approach. We will provide industry standard, in vitro and in vivo assessments that define the pharmacological and toxicological properties of our new prototype drugs. Project aims: 1) Establish what determines the potency and effectiveness of targeted degradation by ULKTACs 2) Optimise the ULK ligand agonist and the in vivo pharmacokinetics of ULKTACs. 3) Optimise and establish the anti-cancer efficacy of MYC-ULKTAC. 4) In collaboration we will expand our platform using in vitro models of neurodegenerative diseases (Parkinson’s disease, ALS), and infection models (HIV-1, Epstein – Barr virus). Our overall aim is to establish AUTOCURE as a platform technology to maximise its clinical and commercial impact and provide industry standard, in vitro and in vivo assessments that define the pharmacological and toxicological properties of new prototype drugs.