Targeted protein degradation using proteolysis targeting chimeras (PROTACs) is a rapidly emerging technology in drug discovery. PROTACs are heterobifunctional molecules that simultaneously bind to a target protein and an E3 ligase. The ternary complex formed from this simultaneous binding promotes transfer of ubiquitin proteins from the E2-E3 complex onto surface lysine residues of the target protein. This tags it for recruitment to the proteasome where it is unfolded and proteolysed into small peptide fragments. This mechanism of action physically removes the protein from cells and constitutes a post-translational chemical knock-down. Many reviews of the area have highlighted potential advantages PROTACs might bring over traditional small molecules, namely: Target all protein functions, including scaffolding; Extended PD, disconnected from PK due to protein resynthesis rates Achieve low clinical dose from catalytic action Unlocking ‘undruggable’ targets via affinity binder Tissue selective pharmacology via E3 ligase distribution Evidence to support these potential advantages in the literature has however remained noticeably scant to date. This presentation will describe the lead optimisation of a series of RIPK2 PROTACs. RIPK2 is a serine/threonine kinase that sits downstream of the pattern-recognition receptor NOD2 and is implicated in a number of autoinflammatory diseases. From this lead optimisation campaign, we will highlight data to support the catalytic nature of PROTAC action as well as disconnects that are observed in the PK/PD relationships for slowly resynthesised proteins such as RIPK2. Collectively, these attractive features can lead to low predicted human doses.

Lead optimisation of a series of RIPK2 PROTACs: Ripping up the rule book

2019 Spring National Meeting

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