Authors

Y Zhang¹; B Gourdet¹; C Pearce¹; J Pickles¹; B Audic¹; P MacFaul¹; H Neal¹; C Scott¹; R Singh¹; L Birch¹; E Pitti¹; E Rodrigues¹; A Brien¹; A Jordan¹; R Hjerpe¹; 
¹ Sygnature Discovery, UK

Discussion

Successful development of bioavailable heterobifunctional degraders (e.g., PROTACs) relies on identifying a combination of ligase recruiter, linker and exit vector that allow formation of a competent ternary complex and target degradation. Conventional single-compound synthesis is time-consuming and poses challenges for selection of degrader components with predictive SAR and ADME properties of the assembled bifunctional compound. Here, we demonstrate an integrated platform that incorporates high-throughput combinatorial chemistry, live-cell kinetic degrader screening and assessment of in vitro DMPK properties (namely characterisation of lipophilicity, metabolic stability and experimental polar surface area). Alongside of this, we have in place computational methods for ternary complex prediction and linker selection. Altogether, our approach facilitates rapid screening and identification of bifunctional lead compounds.