Targeted protein degradation (TPD) is an emergent therapeutic strategy with the potential to circumvent challenges associated with targets unamenable to conventional pharmacological inhibition. Among ...

Chemical inducers of proximity (CIPs) can elicit durable, and often neomorphic, biological effects through the formation of a ternary complex, even at low equilibrium occupancy of their targets. This ...

Chemical inducers of proximity (CIPs) can elicit durable, and often neomorphic, biological effects through the formation of a ternary complex, even at low equilibrium occupancy of their targets. This ...

Noncanonical amino acids are efficiently incorporated into proteins by optimizing mRNA codon usage.

Targeted protein degradation (TPD) is an emergent therapeutic strategy with the potential to circumvent challenges associated with targets unamenable to conventional pharmacological inhibition. Among ...

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NIH Funding Opportunities and Notices in the NIH Guide for Grants and Contracts: Supplemental Guidance to the 2024 NIH Grants Policy Statement: Indirect Cost Rates NOT-OD-25-068. OD

Recent massively-parallel approaches to decipher gene regulatory circuits have focused on the discovery of either cis -regulatory elements (CREs) or trans -acting factors. Here, we develop a scalable ...

Bifunctional molecules such as targeted protein degraders induce proximity to promote gain-of-function pharmacology. These powerful approaches have gained broad traction across academia and the pharm...

Proteolysis targeting chimera (PROTAC) degraders are typically bifunctional with one E3 ligase ligand connected to one target protein ligand via a linker. While augmented valency has been shown with trivalent PROTACs targeting two binding sites within a given target protein, or used to recruit two different targets, the possibility of recruiting two different E3 ligases within the same compound has not been demonstrated. Here we present dual-ligase recruitment as a strategy to enhance targeted protein degradation. We designed heterotrivalent PROTACs composed of CRBN, VHL and BET targeting ligands, separately tethered via a branched trifunctional linker. Structure–activity relationships of 12 analogues qualifies AB3067 as the most potent and fastest degrader of BET proteins, with minimal E3 ligase cross-degradation. Comparative kinetic analyses in wild-type and ligase single and double knockout cell lines revealed that protein ubiquitination and degradation induced by AB3067 was contributed to by both CRBN and VHL in an additive fashion. We further expand the scope of the dual-ligase approach by developing a heterotrivalent CRBN/VHL-based BromoTag degrader and a tetravalent PROTAC comprising of two BET ligand moieties. In summary, we provide proof-of-concept for dual-E3 ligase recruitment as a strategy to boost degradation fitness by recruiting two E3 ligases with a single degrader molecule. This approach could potentially delay the outset of resistance mechanisms involving loss of E3 ligase functionality.

Bifunctional molecules such as targeted protein degraders induce proximity to promote gain-of-function pharmacology. These powerful approaches have gained broad traction across academia and the pharm....