Abstract
Protein–protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic potential in the development of small molecules that modulate these interactions; however, rational design of small molecule enhancers of PPIs remains elusive. Herein, we report the prospective identification and rational design of potent small molecules that enhance the interaction between an oncogenic transcription factor, β-Catenin, and its cognate E3 ligase, SCFβ-TrCP. These enhancers potentiate the ubiquitylation of mutant β-Catenin by β-TrCP in vitro and induce the degradation of an engineered mutant β-Catenin in a cellular system. Distinct from PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, with contacts optimized for both the substrate and ligase within the same small molecule entity. The prospective discovery of ‘molecular glue’ presented here provides a paradigm for the development of small molecule degraders targeting hard-to-drug proteins.
Highlights
IntroductionCorresponding to improvement in binding affinity, NRX-252114 further enhances the ubiquitylation of pSer33/S37A β-catenin peptide to form long ubiquitin chains (Fig. 3d)
Introduction of the cyanoisoindoline inNRX-252114 (6) resulted in another significant gain in potency (EC50 = 6.5 ± 0.3 nM)
We report the prospective identification and rational structure-guided optimization of potent molecular gluelike small molecules intentionally designed to enhance the Protein-protein interactions (PPIs) between mutant β-catenin and β-TrCP that potentiate cellular degradation of an engineered mutant β-catenin in a cellular system
Summary
Corresponding to improvement in binding affinity, NRX-252114 further enhances the ubiquitylation of pSer33/S37A β-catenin peptide to form long ubiquitin chains (Fig. 3d). Another isoindoline analog, NRX-252262 (7) with dimethoxy substitution displays slightly improved potency (EC50 = 3.8 ± 0.2 nM). Compared to the original HTS hit NRX-1532, with an EC50 > 200 μM and only eightfold cooperativity, NRX-252114 and NRX-252262 represent significant improvements in both measures. Improvements in both potency and cooperativity translated into enhanced ubiquitylation of mutant β-catenin peptide, with enhancer molecules potentiating ubiquitin chain formation to levels greater than WT β-catenin peptide
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