Many of the E3 ligases that are currently amenable to TPD are members of the large family of cullin RING E3 ubiquitin ligases (CRL) 4– 6. Degraders are typically categorized either as heterobifunctional PROTACs, or as monovalent molecular glues.
In TPD, small-molecule “degraders” induce the molecular proximity between an E3 ubiquitin ligase and a protein of interest (POI), leading to the poly-ubiquitination and proteasomal degradation of the latter 3. One of the most powerful embodiments of proximity-inducing agents with immediate therapeutic potential is the concept of targeted protein degradation (TPD). Mechanistically, the involved small molecule often co-opts the function of one protein by inducing a naturally non-occurring interaction with another protein 2. At its core, it encompasses therapeutic modalities, often small molecules, which induce the proximity between macromolecular structures to prompt a novel functional response of potential therapeutic relevance. Proximity-inducing pharmacology is a therapeutic paradigm currently met with high enthusiasm and is experiencing a renaissance both in academia and the pharmaceutical industry 1. In sum, we present a fast and experimentally widely accessible methodology that empowers the characterization of small-molecule degraders and informs on associated resistance mechanisms. Moreover, we identified and validated hotspots mutated in patients that relapse from degrader treatment. Biophysical and structural validation suggest that hotspot mutations frequently converge on altered ternary complex assembly. Intersection with deep mutational scanning data revealed hotspots that are either conserved, or specific for chemically distinct degraders or recruited neosubstrates. Here, we employ haploid genetics to show that hotspot mutations cluster in the substrate receptors of the hijacked ligases and find that type and frequency of mutations are shaped by the essentiality of the harnessed ligase. Until now, their identification was driven by structural methods with limited scalability. Understanding disruptive mutations in functional hotspots informs on the architecture of the underlying assembly, and highlights residues prone to cause drug resistance.
Based on the structure of the degrader and the neosubstrate, different E3 ligase interfaces are critically involved in this process, thus forming defined “functional hotspots”. Targeted protein degradation is a new pharmacologic paradigm established by drugs that recruit target proteins to E3 ubiquitin ligases via a ternary ligase-degrader-target complex. The content of the present website is protected by copyright which is the exclusive property of Mortgage Planners – Mortgage Agency.
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