POP/FAP as potential targets against cancer
Nearly 1 in 2 Canadians are expected to develop cancer in their lifetimes. Although cancer is very complex, several studies link two homologous serine proteases: prolyl oligopeptidase (POP) and fibroblast activation protein alpha (FAP) to angiogenesis and tumor growth, respectively. The similarity and biological implication of these two enzymes therefore demonstrate a viable strategy to treat cancer. In our research group, we utilise a combination of computational methods and advanced synthesis to discover and develop compounds that would act as reversible covalent inhibitors against these targets.
So far, we have carried out virtual screenings to discover novel scaffolds; after virtually and synthetically modifying hits from these screenings and obtaining promising structures, we have successfully discovered first-of-their-kind dual covalent inhibitors. Our first series and subsequent optimizations were optimized into scalable, two-step syntheses and gave dual inhibitors of nanomolar potency. We have since progressed onto exploring constrained peptidomimetics to target these two proteases.
Our chiral, bicyclic structures have exhibited very promising activity, outperforming past clinical drug candidates. Our current lead dual inhibitors exhibit nanomolar potency in vitro and show activity against tumours in vivo in mouse models. Using our group’s combined expertise in medicinal chemistry, biochemistry, and computational chemistry, we intend to develop our most promising compounds into candidates for clinical trials.
Keywords : · Computationally-aided Drug Design · Dual inhibition · Organic synthesis · Covalent inhibition
Key people involved in the project : Anne Labarre (graduate student), Jessica Plescia (PhD '20), Nicole Blaine (undergraduate student, '19-'20), Stephane De Cesco (PhD '16), Gaelle Mariaule (PDF '14-'15), Naela Janmamode (MSc '18), Damien Hedou (PDf '16-'17), Caroline Dufresne (alumna), Sylvain Rocheleau (alumnus), Sebastien Deslandes (PDF '11-'12), Janice Lawandi (PhD '10)
Key publications related to the project : here