Aza Pyrrolidine MtPTACs for the Treatment of Pancreatitis and other Degenerative mPTP Related Diseases

About the Project

This drug discovery project will set out to inhibit a key protein, known as cyclophilin D, using a lead optimisation approach of second generation inhibitors developed at Liverpool. The project will comprise synthetic organic chemistry, computational chemistry and analysis of in vitro and in vivo pharmacological efficacy data in parallel with pharmacokinetic analyses.

This programme focuses on developing novel the first MtPTAC (Mitochondrial Protease Targeting Chimera) based therapeutic for acute pancreatitis, a disease with ~50,000 UK cases annually and costs exceeding £2B. No current therapy halts disease progression or occurrence. In collaboration with Professors Robert Sutton and Rishi Mukherjee (Liverpool NIHR Pancreas BRU), we have optimized mitochondrial permeability transition pore (mPTP) modulators targeting cyclophilin D, whose inhibition preserves mitochondrial function (Nature 2005, 434, 658). Our medicinal chemistry work has produced single-digit nanomolar Cyc D inhibitors (e.g., GLQ-01-6-9, J. Med. Chem., 2025, in press) showing in vitro and in vivo efficacy (Fig. 1A). The patented lead series features a novel aza-pyrrolidine headgroup that preorganizes the inhibitor for precise Cyc D binding.

Proposal: The mitochondrial protease targeting chimera MtPTAC strategy for modulating the mitochondrial permeability transition pore (MPTP) via CycD proteolysis is expected to enhance efficacy since (i) catalytic degradation of CycD offers greater efficacy than stoichiometric inhibitors, and (ii) provides a longer-lasting protective effect through sustained CycD removal. X-ray crystallography (Fig. 1B) and computational modelling has identified a solvent-accessible linker point, within our inhibitors, suitable for attachment of caseinolytic protease (ClpP) ligands without disrupting CycD binding. The synthetic chemistry has been designed to enable modular linkage to ClpP ligands via click chemistry or straightforward metal-catalyzed coupling (SLAS Discovery, 2021, 26, 4, 484). As the MPTP is implicated in neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and ALS, this PROTAC-based approach will also be evaluated in in vitro ALS models (existing collaboration with Hasnain group), expanding therapeutic potential.

This integrated synthesis, modelling, and biology programme accelerates the design-make-test-analyse cycle, optimising DMPK properties and chemical space exploration. Its success will showcase PROTAC optimisation in drug discovery, generating high-impact outcomes and attracting potential future research council and industry funding.

Training: The student will be trained in synthetic medicinal chemistry (PON, GN) and molecular modelling (NGB), gaining multidisciplinary experience through work in chemistry, biological and computational labs. This comprehensive training, supported by an experienced supervisory team with >70 successful PGRs, will significantly enhance the student’s employability in scientific careers

This UKRI funded Studentship will cover full tuition fees (for 2025-26 this is £5,006 pa.) and pay a maintenance grant for 3.5 years, at the UKRI standard rates (for 2025-26 this is £20,780 pa.) The Studentship also comes with access to additional funding in the form of a Research Training Support Grant to fund consumables, conference attendance, etc.

UKRI Studentships are available to any prospective student wishing to apply including both home and international students. While UKRI funding will not cover international fees, a limited number of scholarships to meet the fee difference will be available to support outstanding international students.