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.

We discovered a covalent GSTP1 inhibitor that functions as a molecular glue via a ligand-induced protein tethering (LIPT) mechanism. Electrophilic modification of GSTP1 induces reversible disulfide-dependent protein–protein interactions enriched in nuclear and splicing factors. LIPT relocalizes splicing factors, altering lipid metabolism and suppressing proliferation in LIPT-sensitive cancer cells. These findings highlight covalent molecular glues as a strategy to modulate neo-PPIs and cancer metabolism.

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.

Regulated Induced Proximity Targeting Chimeras (RIPTACs™) are a novel small‑molecule therapeutic modality that selectively induce cancer cell death by tethering a tumor‑specific protein to a pan‑essential protein, forming a lethal ternary complex. This “hold‑and‑kill” mechanism disables essential protein function specifically in tumor cells, independent of oncogenic drivers and resistant to known escape pathways. Preclinical and early clinical data show oral bioavailability, favorable safety, and broad antitumor activity. HLD‑0915 demonstrates efficacy in metastatic castration‑resistant prostate cancer, while HLD‑0117 shows potent activity in endocrine‑sensitive and resistant breast cancer and is advancing clinically.

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.

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.