We engineered bispecific antibody degraders to achieve tissue-restricted degradation of cell-surface receptor targets. These molecules drive receptor internalization and lysosomal clearance while minimizing toxicity and enhancing specificity. They can also be adapted into next-generation ADCs to deliver potent, selective efficacy. This versatile platform integrates cell surface receptor degradation with payload delivery, advancing safer and more effective antibody-based degraders.

REM-422, a first-in-class mRNA Degrader of the MYB Oncogene, is being developed by Remix Therapeutics for the treatment of ACC and AML/HR-MDS. The REMaster platform identifies compounds that address undruggable, high unmet medical-need targets. These next-generation drug discovery programs are enabled by a suite of biophysical assays and expand the scope of pharmacologically tractable splice modulator modalities.

LYMTACs are heterobifunctional small molecules that harness lysosomal membrane proteins (LMPs) to relocalize and degrade otherwise undruggable membrane proteins. We demonstrate that oncogenic KRASG12D signaling can be effectively inhibited by LYMTACs, which act through both target relocalization and degradation. Extending this approach across diverse targets and LMPs, we establish LYMTACs as a versatile small molecule-based platform for targeted lysosomal degradation of challenging membrane proteins, expanding therapeutic possibilities.

Roughly 75% of disease targets are considered difficult-to-drug or insufficiently drugged. Molecular glue degraders provide an unique approach to engage these targets. I will use case studies from Degron’s internal pipeline programs to illustrate the power of molecular glue degraders to overcome such challenges and even illuminate novel target biology in disease treatment.

Monovalent, Lipinski-compliant molecular glue-class protein degraders are highly prized but there are few reliable methods for their discovery. In this talk, we describe the establishment of an in vitro assay that allows DNA-encoded libraries of bead-displayed small molecules to be screened for the ability to trigger the poly-Ubiquitylation of a co-immobilized target protein by Ubiquitin (Ub) ligases. We describe a first-generation system that employs a user-chosen, purified E3 Ub ligase as well as a second-generation assay that employs a cell extract as the source of enzymes.

We present ToRNeDO, SyntheX's empirical, cell-based platform that revolutionizes molecular glue discovery by eliminating reliance on serendipitous discoveries. ToRNeDO enables functional selection of molecular glues that use specific target/ligase pairs. The system is also used to map novel degrons for rational glue design. Using this platform, we discovered highly selective molecular glues against previously untargeted effectors and E3s, demonstrating ToRNeDO's potential to unlock new therapeutic strategies through systematic, directed molecular glue development.

Key topics of discussion include the power of high-throughput proteomics for unbiased discovery of novel neosubstrates, the application of AlphaFold-like algorithms to predict ternary complex structures, and the use of direct-to-biology strategies to expand the chemical space. These integrated approaches are paving the way for the next generation of molecular glue therapeutics.

snRNAs are required for the structure and function of the spliceosome. Here we report a potent and selective covalent ligand that targets TOE1, a 3’ RNA exonuclease, only when bound to the Sm complex. We find that this compound acts as a “molecular clamp”, dramatically stabilizing TOE1-Sm complex interactions and triggering the excessive trimming of snRNA 3’ termini in cells. Our findings may have therapeutic implications for splicing-related diseases.

This talk will describe microfluidics-enabled cellular phenotypic DEL workflow—MicDrop. We will introduce cellular DEL screen in droplets, followed by results from a cellular protein degradation screen with a validation library, as well as another set of screens with a prospective library. Our results show the benefits of bead replicates and how this new paradigm of DEL screen can accelerate the field of molecular glue discovery for TPD and beyond.

Herein, we report the discovery of PLX-66140, a potent CDK2 cereblon-based degrader. Using Plexium’s picowell DEL screening platform, we identified multiple CDK2 degrader hits. Medicinal chemistry optimization resulted in the identification of a selective and orally bioavailable drug development candidate. Oral administration of PLX-66140 in tumor-bearing mice demonstrated robust target degradation and enhanced anti-tumor activity over ATP-competitive inhibitors in multiple CCNE1-amplified mouse xenograft models at well tolerated doses.