Targeted Protein Degradation: Challenges And Opportunities

By Indrani Sarkar, PhD, Senior Director, Assay Development and Screening, Discovery Biology Solutions, Aragen Life Sciences, India

Proteolysis targeting chimera (PROTAC) is a novel drug development strategy that has brought a paradigm shift as a therapeutic modality. This field has evolved greatly in recent years in drug discovery, riding a wave of new tools, novel algorithms, and growing investment to more widespread studies.

Degradation is a significantly different modality from small molecule inhibition as PROTACs have a catalytic mode of action, event-driven pharmacology, and ability to target undruggable proteins with shallow pockets like kirsten rat sarcoma virus (KRAS), non-enzymatic scaffolding proteins, multicomponent protein complexes like the BAF chromatin remodeling complex and transcription factors.

Effectively and efficiently understanding the degradation mechanism of action and how different E3 ligases can be leveraged requires having appropriate tools and technologies in place, as well as insight into which assays are to be developed within a screening funnel.

Based on the scope of our collaborations, Aragen offers flexible solutions to accommodate the varying queries and emphases of our partners. We provide the reagents, tools and technologies to design an effective strategy to meet the project goals.

Our strategy is guided by the critical decision-making factors. Is plenty of prior knowledge already available about the target (e.g., it has been validated), or is its functionality a mystery? For example, if the target is novel or the downstream effects are not well-known, what is the differentiation in functional response if inhibited or degraded? We design appropriate functional and mechanistic assays to understand target biology and the outcome of target degradation.