Nature Chemical Biology studies advance systematic discovery of molecular glues
Two Nature Chemical Biology studies described new routes to molecular glue discovery. One identified ZZ1 and YPEL5-linked CTLH recruitment, while another found an ENL degrader in leukemia cells.
Molecular glue discovery advanced in two Nature Chemical Biology studies that described new ways to induce targeted protein degradation. One study reported chemocentric discovery of ZZ1, a BET-family protein degrader and a prodrug of a negatively charged glue, while another described high-throughput ligand diversification to discover chemical inducers of proximity and identified a compound that selectively triggers degradation of ENL in leukemia cells.
Small molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways and tools for agriculture. Molecular glue degraders promote binding between ubiquitylating enzymes and neosubstrates, ultimately resulting in targeted protein degradation, and have drug-like properties, induce targeted protein degradation at low compound concentrations by acting catalytically, do not require preexisting ligands for both recruited proteins and can recruit partners without drug-binding pockets.
The study on charged molecular glue discovery said molecular glue degrader discovery for predefined targets is a major challenge in contemporary drug discovery. It reported that ZZ1 activation unmasks a sulfinic acid that binds the modular CTLH ubiquitin ligase complex through a basic pocket in its YPEL5 subunit, and said the findings demonstrate a previously unrecognized capacity of YPEL5 to recruit CTLH substrates and enable the discovery of molecular glue degraders for exceedingly common acidic and basic degrons.
That study also said molecular glue degraders bearing complementary charges are needed to access E3 ligase systems dependent on electrostatically driven substrate binding. It added that such molecules have not emerged from previous molecular glue degrader discovery campaigns, largely because of difficulties in developing cell-permeable charged small molecules.
The second study took a systematic approach to the discovery of new molecular glues by starting from a small molecule that already binds to a target protein and generating thousands of chemical variants by systematically attaching different molecular building blocks. The compounds were screened directly in living cells, without prior purification, using a sensitive assay that reports whether the target protein is being degraded.
That work focused on ENL, a protein that plays a central role in certain forms of acute leukemia. From several thousand tested compounds, the team identified a molecule that efficiently and selectively triggers degradation of ENL in leukemia cells; further analyses showed that the compound primarily affects ENL and downstream gene programs controlled by this protein, leading to a strong reduction in the growth of ENL-dependent leukemia cells.
The study said the compound acts through a cooperative mechanism characteristic of molecular glues: it first binds ENL and then creates a new interaction surface that recruits a cellular ubiquitin ligase, which marks ENL for degradation. Beyond the specific example of ENL, the researchers said the study demonstrates a broadly applicable discovery strategy by combining high-throughput chemistry with functional screening in cells and showing how the identification of molecular glues can be transformed from a serendipitous process into a systematic workflow.