We are developing a next-generation small molecule–drug conjugate (SMDC) designed to overcome the penetration limitations of conventional ADCs. By targeting a tumor-associated antigen enriched in the tumor microenvironment, this novel modality enables deep tumor infiltration and potent anti-tumor activity in complex TME settings.

My laboratory develops scalable, quantitative platforms to study targeted protein degradation. By combining fluorescent stability reporters, pooled CRISPR screening, and high throughput flow cytometry, we uncover diverse small molecule-induced degradation mechanisms and expand target scope. A major focus is CRBN, a highly plastic E3 ligase. Using large libraries and ultrasensitive degron discovery methods, we define rules of substrate recognition and identify targets often missed by conventional proteomics.

We present an integrated platform combining AI with structural proteomics to inform the rational design of protein degraders. The talk highlights specific strategies for optimizing lead compounds, featuring a deep dive into preclinical data from Protai's KAT6 degrader program.

We will discuss how we apply state-of-the-art high-throughput proteomics to discover molecular glue hits and apply AlphaFold 3-like folding software to predict the structures of molecule glue induced ternary complexes.

While large strides have been made towards de novo design of molecular glue degraders (MGDs), library screening of cereblon ligands remains essential. We present here our MGD discovery platform that combines a hypothesis-driven second-generation molecular glue library with high-throughput deep proteomics screening method. The screening data for >4,000 compounds will be discussed and exemplified with several degraders of novel neosubstrates with non-canonical ternary complex binding mode, as determined by cryo-EM.

We present a screening strategy for the discovery of both degradative and non-degradative macrocyclic molecular glues. Highlights will include development of assays for the discovery of kinase- and phosphatase-recruiting ligands that do no inhibit these enzymes (preferable for glue development) from one bead one compound libraries; description of a fragment-based drug development-like workflow for macrocyclic glue discovery that does not require the synthesis of extremely large libraries and an application of this technology to the creation of phosphatase recruiting chimeras (PHORCs) that engage the PTP1B phosphatase.

We are industrializing molecular glue discovery to drug previously intractable targets lacking conventional binding pockets. By expanding chemically enabled E3 ligases and building a 500,000-compound glue-focused library, we enable target-centric and -agnostic screening. Proximity proteomics and Picowell RNA-seq identified VHL-based degraders dCASP2 and dGEM3, demonstrating programmable ternary complex formation and selective target degradation, advancing the goal of reaching any target, every time.

The presentation will address how TRIMTECH is leveraging its proprietary platform of small molecule TRIMTAC degraders to recruit the novel E3 ligase TRIM21 to the surface of intracellular protein aggregates. Selective degradation of multimeric forms of proteins is achieved via a unique clustering activation mechanism (ligase to ligase; proximity) that spares the monomeric protein, demonstrating the potential of this next generation targeted protein degradation approach for the development of targeted therapies for proteophathic aggregates in neurological disorders.

ALK inhibitors have improved outcomes in ALK+ non-small cell lung cancer but remain limited by off-target toxicity, and resistance mutations. This work describes the discovery of TRI-611, a brain-penetrant CRL4CRBN molecular glue degrader that addresses resistance by recruiting ALK via a degron distal to the orthosteric ATP binding site. TRI-611 drives tumor regression in pre-clinical mouse xenograft models with daily oral dosing and is currently in Phase I/II clinical trials.

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.

This talk will challenge your view that finding a novel ligase for a target is difficult, and that discovering a molecular glue is mostly based on serendipity and a very challenging task. Not anymore. We will show how smart (sorry, not AI based) modeling can deliver novel ligases and molecular glues in a fast and very efficient manner.

Current extracellular targeted protein degradation (eTPD) strategies primarily rely on recycling receptors and lysosomal trafficking for internalization and degradation. Here, we developed bispecific antibodies that recruit membrane-bound proteases to proteins of interest, enabling their “degradation” them via enzymatic shedding. Additionally, the induced proteolysis releases soluble ligands that may influence downstream cellular processes. This approach provides a new mechanism of eTPD and broadens the scope of antibody-based therapeutics.

Targeted protein degradation has emerged as a powerful therapeutic strategy but has been largely restricted to intracellular targets. I will present our work on degraders for extracellular and membrane proteins that exploit lysosome-targeting receptors with distinct tissue-expression profiles and show promising activity in vitro and in vivo. I will also describe a general glycoengineering strategy for site-selective antibody conjugation, enabling homogeneous therapeutic conjugates.

Gene transcription is often controlled by complexes consisted of several proteins, including transcriptional factors and co-activators, among others. We propose to develop hetero-bifunctional domain alteration chimeras (DALTACs) to target gene transcriptional complexes as a new therapeutic strategy. As compared to conventional small-molecule inhibitors and degraders, DALTACs have the major advantages in concurrently targeting two different proteins and are capable of achieving exceedingly high potency, specificity and efficacy. Extensive medicinal chemistry optimization can yield orally active and highly efficacious DALTACs suitable for clinical development.

Targeted protein degradation has largely relied on the ubiquitin–proteasome system, limiting accessible targets. Here, we introduce methylarginine targeting chimeras (MrTACs), a new class of small molecules that recruit PRMTs to install lysosome-targeting degrons. MrTACs induce robust, selective degradation of diverse and previously intractable proteins via microautophagy. This work establishes lysosomal proteolysis as a complementary, therapeutically viable pathway, expanding the degrader toolbox and enabling access to challenging disease-relevant targets.

ARID1B is a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex and a key regulator of gene accessibility. Its lack of ligandable pockets has long rendered ARID1B an undruggable target. Cancers with ARID1A loss-of-function mutations—including endometrial, ovarian, and gastric tumors—show a strong synthetic lethal dependency on ARID1B, highlighting its therapeutic potential. Using structure-based design and binder discovery, we identified the first selective ARID1B-binding chemical series and developed VHL- and CRBN-recruiting degraders that induce ARID1B loss. These findings establish targeted ARID1B degradation as a promising strategy for ARID1A-mutant cancers and provide a framework for drugging previously intractable proteins.

The majority of approved ADCs rely on a small number of payload classes, including topoisomerase and tubulin inhibitors. Resistance to these payloads is increasingly recognized as a limitation of existing ADCs. Over the past few years, we have developed many protein degraders with sub-nanomolar potency. Conjugating these degraders to antibodies yields degrader-antibody conjugates (DACs) with improved therapeutic indices. In this talk, I will present two of our DAC programs.

Rationally designed dual SMARCA2/4 degrader payloads demonstrated potent, selective target degradation and strong antiproliferative activity across multiple cancer cell lines.  Physicochemical properties suitable for DAC development were maintained, and the designed payloads were incorporated into state-of-the-art linker architectures.  Subsequent conjugation and evaluation across multiple antigens demonstrated the potential of precision degrader antibody conjugates (pDACs) to advance next-generation precision medicine.

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.

Recent advances in peptide display technologies enable rapid identification of high‑affinity macrocyclic peptides, yet their poor membrane permeability often limits therapeutic utility. I present a “Peptide‑to‑Small Molecule” strategy that translates peptide binding information into drug‑like small molecules through pharmacophore extraction and structure‑guided de novo design. Using some case studies, I demonstrate how this approach/concept enables discovery of cell‑active small‑molecule inhibitors for traditionally challenging targets.

FGFR2 alterations drive several cancers, including gastric, breast, and intrahepatic cholangiocarcinoma (ICC), but current FGFR inhibitors show limited benefit. We developed biparatopic antibodies that bind FGFR2, demonstrated strong potency in FGFR2-driven and fusion-positive ICC models, and also showed activity against resistant FGFR2 mutations, supporting their therapeutic promise for FGFR2-driven cancers.

CD40L is a clinically validated immunology target with no small-molecule pocket. Oral, non-antibody Spiroligomer™ peptidomimetics engage this flat protein-protein interface. Starting from DEL hit 02-017, we modularly optimized the inter-spiro linker and sidechains over two rounds, improving Kd from ~10–15 µM to 0.96 µM (lead 02-067) and IC₅₀ from 8.4 to 1.2 µM—a greater than tenfold gain.

Targeted degradation of integrins was investigated using two engineered degraders: one based on LYTAC (mediated by the asialoglycoprotein receptor, ASGPR) and one based on AbTAC (mediated by a membrane-bound E3 ligase). Degrading cell-surface αv integrins, rather than merely blocking their interactions with the extracellular matrix (ECM), produced a stronger anti-proliferative effect and greater suppression of tumor cell growth. Notably, the two degrader modalities engaged distinct downstream oncogenic signaling pathways, suggesting mechanism-specific effects beyond simple target removal. Our work demonstrates targeted degradation as a promising, and potentially superior, approach to cancer therapy relative to conventional blockade. We will also share lessons learned from degrader design and structure-activity relationship (SAR) studies, along with mechanistic insights from in vivo investigations.

Breakthroughs in biology, omics, AI/ML, data, and structural sciences are converging with novel chemistries to expand both the drug modality repertoire and accessible target space. These advances promise a future in which every target, regardless of structural class, may be matched to the optimal modality at unprecedented speed and precision. In turn, molecular modality matching to target and indication, has become a critical early strategic decision in drug discovery.