A degron blocking strategy towards improved CRBN recruiting PROTAC selectivity

The different layers of complexity in PROTAC design have slowed the broad implementation of this novel pharmacological approach. Given the challenges and opportunities of CRL4CRBN hijacking PROTACs we set out to identify and develop broadly implementable strategies to generate PROTACs with improved specificity for their targets. We used structural analysis of known neo-substrate degrons to generate “degron blocked IMiD” analogues and validated that they did not degrade any known neo-substrates using quantitative proteomics. We then applied this strategy to a known BRD9 PROTAC (dBRD9-A) to generate a degron-blocking analogue with a specific degradation profile.