We present assessments of the minimal binding domains of transcription factors IKZF2, WIZ, and counter target SALL4 revealing that each of these proteins interacts with cereblon:glue complexes in a unique manner. In addition, we explore the known binding mode of GSPT1, which interacts with cereblon through a G-loop, and contrast that with the unique binding mode of TBK1, a kinase involved in innate immunity.

Proteomics can be an invaluable tool in drug discovery, as it can provide target agnostic information on drug-induced, proteome-wide abundance changes, but a disadvantage is its throughput. To combat this, we developed a workflow in 384-well plates, combining this with faster data acquisition to achieve higher throughput proteomics. We applied this platform in the TPD space to screen compound libraries for hit identification and profile leads to understand off-target selectivity.

Inhibition of PLK1 may be key to overcoming resistance to androgen-blocking treatments that result in Castration Resistant Prostate Cancer (CRPC) providing new therapeutic options. Using the REPLACE strategy, we found compounds that bind tightly to PLK1 and induce its degradation Through our hit-to-lead conversion studies we have identified an abbapolin degrader with potent on target cellular engagement of PLK1, good oral pharmacokinetics. and antitumor efficacy in prostate xenografts.

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 report the identification and optimization of first-in-class selective ARID1B degraders that drive targeted protein degradation. Using our platform and structure-based design, we developed VHL- and CRBN-based molecules that induce robust ARID1B degradation via the ubiquitin-proteasome system. These compounds demonstrate on-mechanism activity, high selectivity, and downstream gene modulation. Our work lays the foundation for ARID1B degradation as a promising strategy to exploit synthetic lethality in ARID1A mutant cancers.

Estrogen receptor (ER)-targeted RIPTACs selectively inactivate BRD4 in ER+ breast cancer, including post-CDK4/6i resistance settings. These agents show potent in vitro anti-proliferative activity across ER wild-type and mutant models, strong in vivo efficacy in CDX and PDX models, and lack endometrial agonism. RIPTACs offer a promising, tumor-selective therapeutic approach with broad applicability in metastatic breast cancer and anticipated Phase 1 start in early 2026.

Targeted protein degradation is transforming how we probe and manipulate the proteome. My talk will showcase how we leverage degradation-based technologies including the dTAG platform to interrogate oncoproteins, mRNA translation factors, and kinases that drive aggressive viral-driven and solid tumor cancers. These studies demonstrate how precise, rapid protein degradation accelerates target validation, reveals functional insights, and expands the druggable proteome.

Ternary Therapeutics has developed a computational design platform for molecular glues of any protein-protein interaction. This platform has been applied to discover novel molecular glue degraders, activators, and non-degrading inhibitors, which the company is progressing through their drug-discovery pipeline. This presentation will focus on the design and validation of the computational platform.

This talk will demonstrate how a structural proteomics and AI integrated framework informs degrader design. It will showcase lead optimization strategies to enhance the efficacy and selectivity of degraders and preclinical results from Protai’s KAT6 degrader program will be presented as a case study.

Oral bioavailability of TPDs, especially larger sized bifunctional molecules (i.e. PROTAC), is one of the most challenging properties to be optimized. In this study, a comprehensive in vivo data set for CRBN-based PROTACs was collected from public domain and 2D/3D descriptors were developed to establish predictive models for oral bioavailability prediction. We address the different behavior of predictive models on different types of animal models, like mouse and rat models.