Protein-protein interactions (PPIs) play a crucial role in nearly all cellular processes. Protein complexes have been implicated in many debilitating human diseases, from cancer to viral infections. PPIs generally contain broad, shallow, and relatively featureless binding sites, hence they have historically been perceived as ‘undruggable’ targets in drug discovery. The research team led by Dr. Batey has developed a platform that can rapidly identify lead compounds for the disruption of PPIs, while not necessarily relying upon crystal structure. To identify such leads, the team first synthesizes a library of small molecule fragment-peptide conjugates (SMPCs), which act like a fishing-rod bait model when screened against the target of interest using simple binding assays.Once leads are identified, substitution of the peptidic portion of the SMPC with a library of small molecule building blocks generates a library of ‘non-peptidic’ small molecule inhibitors that can be further optimized into potent drugs.
The team’s ambition is to develop the high throughput and robust SMPC methodology to rapidly identify lead compounds for the disruption of a broad range of PPIs. This higher throughput technology will then be applied to identify novel and non-peptidic cell-permeable small molecule inhibitors for four challenging PPI drug targets including IAP, C-Myc, epigenetics and immuno-oncology targets. Work will include optimization of SMPC libraries synthesis, biochemical screening and hit validation, small molecule lead conversion via combinatorial library generation and cell permeability studies. Successful completion of these steps for all four targets will mark the complete development of the technology platform and its commercial readiness.
University of Toronto