Drugging the Undruggable Symposium Agenda

Welcome and introduction

08:30 a.m. - 08:35 a.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

When molecular glue meet orthosteric inhibitor

Orthosteric inhibitors block enzyme active sites through direct competition, making substrate-dependent potency seem inherently unlikely. This talk will discuss how CSN5i-3, an orthosteric inhibitor of the COP9 signalosome, unexpectedly operates via a molecular glue mechanism — simultaneously occluding the substrate cleavage site while cementing the NEDD8–CSN5 interaction. This cooperative trimolecular assembly sequesters the inhibitor at its binding site, establishing orthosteric molecular glue inhibitors as a new class of substrate-dependent enzyme antagonists.

08:35 a.m. - 09:10 a.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Targeting transcriptional factors

Transcriptional factors (TFs) represent a large class of therapeutic targets but direct targeting TFs using small-molecules has proven to be very challenging in most of the cases. Induced targeted protein degradation has become a powerful strategy to target TFs. Additionally, hetero-bifunctional, non-degrader small-molecules can be successfully employed to target TFs. In this lecture, Dr. Shaomeng will present some of their research in the development of highly potent and effective degraders and non-degraders to target transcriptional factors.

09:10 a.m. - 09:30 a.m. 

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Targeted degradation of eIF1A in PDAC halts nascent translation and activates stress responses

This talk will discuss eIF1A degradation. EIF1A is a translation initiation factor that is essential for protein synthesis and cell proliferation. To study the immediate consequences of its loss, eIF1A degradation tag (dTAG) systems were engineered in pancreatic ductal adenocarcinoma cell lines. These models revealed that eIF1A depletion rapidly halts nascent protein synthesis and sequentially activates ribotoxic and integrated stress response pathways, providing new insights into early cellular responses to eIF1A loss.

09:30 a.m. - 09:40 a.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Moderated by: Champak Chatterjee, PhD

Featuring all speakers from session 1 + audience

09:40 a.m. - 10:00  a.m. 

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Refreshments Available

10:00 a.m. – 10:20 a.m.

Weintraub Building Great Hall
Fred Hutch Cancer Center

Targeting therapeutic vulnerabilities in cancer through transferrin receptor 1–mediated protein degradation

This talk will introduce the Zhou Lab’s work on TransTAC platforms for targeted membrane protein degradation in cancer. Dr. Zhou will highlight applications in EGFR-driven lung cancer, the extension of this approach to challenging GPCR targets, and efforts to exploit iron uptake pathways as therapeutic vulnerabilities in cancer.

10:20 a.m. - 10:40 a.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

MrTAC is a lysosomal targeted degrader of the intracellular proteome

This talk presents MrTACs—bifunctional small molecules that exploit the lysosomal methylarginine degron to drive potent degradation of disease-relevant proteins through a fully endogenous and therapeutically viable platform. 

10:40 a.m. - 11:00 a.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Expanding the chemical tractability of the human proteome

Chemical probes offer a valuable way to directly interrogate the function and disease-relevance of proteins and can also serve as valuable leads for drug development, yet most proteins in the human proteome lack small-molecule ligands that can serve as probes. More generally, the boundaries, if any, on the potential druggability across native proteomes remains poorly understood. Dr. Parker will describe his lab’s efforts to develop powerful chemical proteomic strategies to broadly map chemically-tractable proteins directly in cells, and how this information can be advanced into useful chemical probes for targets that play critical roles in disease.

11:00 a.m. - 11:20 a.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Moderated by: Bob Eisenman, PhD

Featuring speakers from session 2, morning keynote speaker + audience

11:30 a.m. - 11:50 a.m. 

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

11:40 a.m. - 12:25 p.m. 

High-throughput mechanistic profiling of protein–small molecule interactions

This talk will explore how Label-seq, a high-throughput sequencing-based method, can illuminate the mechanisms by which small molecules modulate intracellular protein function. A few illustrative test cases will be briefly described to highlight how Label-seq readouts can reveal complex modes of action that are difficult to capture through conventional assays.

12:25 p.m. - 12:45 p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Rewiring the proteome with induced proximity

This presentation will provide an overview of the Taipale Lab's unbiased approaches for discovering proximity-dependent modulators of cellular pathways, including protein degradation, transcription, and DNA damage.

12:45 p.m. - 01:05 p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Structure-free, AI-guided discovery of small molecule inhibitors for intrinsically disordered transcription factors

This talk will introduce new approaches to drugging transcription factors. Transcription factors and other gene regulators have been historically challenging for small molecule drug discovery due to their intrinsic disorder along with a lack of suitable assays for measuring their native activity. Talus Bio has developed the first native, unbiased, functional measurement technology for gene regulators, and has used it to profile over 150M interactions between these proteins and small molecules. Leveraging this data, they have built structure-free AI models that accelerate the identification of novel TF modulators and the optimization of these modulators towards clinical candidates. 

01:05 p.m. - 01:15 p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

De novo designed miniproteins for selective kinase modulation

De novo protein design enables precise, genetically encoded control over protein kinases by targeting allosteric surfaces on the kinase domain. This talk will discuss work at the Institute of Protein Design developing a computational and experimental pipeline to design compact miniproteins that bind kinase domains and inhibit or activate activity, using focal adhesion kinase (FAK) as a test case. Potent, selective modulators are validated with biochemical assays and structural analysis and show rapid redesign to generate Src-targeted inhibitors.

01:15 p.m. - 01:25  p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Moderated by: Alice Berger, PhD

Featuring speakers from session 3 + audience

01:25 p.m. - 01:45 p.m. 

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Refreshments Available

01:45 p.m. - 02:00 p.m.

Weintraub Building Great Hall
Fred Hutch Cancer Center

Towards new cancer medicines with degraders of chromatin regulatory proteins

ARID1B, a core component of the SWI/SNF chromatin remodeling complex, has long been considered undruggable due to the absence of known binders and lack of ligandable pockets. Striking dependency on ARID1B is observed across multiple cancer indications harboring ARID1A mutations, including endometrial, ovarian, and gastric cancers. Dr. Daniels reports the discovery and optimization of first-in-class selective ARID1B degraders that exhibit on-mechanism activity, high selectivity, and downstream transcriptional modulation. This work establishes ARID1B degradation as a promising therapeutic strategy and provides a blueprint for targeting previously intractable chromatin remodelers.

02:00 p.m. - 02:20 p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

From undruggable targets to human therapeutics: clinical lessons from bexobrutideg

This presentation will highlight how targeted protein degradation is enabling the translation of previously “undruggable” targets into clinically meaningful therapies, using bexobrutideg as a case study. Drawing on emerging clinical data, it will illustrate how degradation of BTK can deliver deeper and more durable pathway suppression than inhibition alone, including activity across resistance mutations and in challenging disease settings such as CNS involvement. The talk will also explore how the catalytic mechanism of degraders enables robust efficacy at lower exposures, contributing to a favorable safety and therapeutic index. Together, these findings establish targeted protein degradation as a differentiated therapeutic modality with the potential to redefine treatment paradigms in B-cell malignancies and beyond.

02:20 p.m. - 02:40 p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Co-opting the ubiquitin system for therapeutic benefit

The goal at Lyterian is to co-opt protein homeostasis effectors to correct the dysregulation of challenging therapeutic targets. Their efforts are focused on neurodegeneration targets for which there is a clear rationale for homeostatic regulation over target inhibition. Dr. Wertz will discuss strategies to co-opt endogenous cellular machinery, highlight mechanisms for how selective targeting can be achieved, and review the cellular and physiological consequences of target regulation, with an emphasis on maximizing safety and therapeutic benefit for patients with unmet medical needs.

02:40 p.m. - 03:00 p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Any target every time: how multispecific drugs are revolutionizing pharmacotherapy

Rapid clearance of drugs, functional redundancy of targets, on-target/off-tissue toxicity, and lack of druggable features in targets (i.e. undruggability) are four major challenges that biology poses to drug developers. This talk will describe how a new generation of multispecific drugs enable drug designers to surmount these challenges. In particular, this presentation will focus on the rapidly-emerging induced proximity drugs that exert their pharmacological action by linking otherwise undruggable targets to powerful, natural effector mechanisms.

03:00 p.m. - 03:35 p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Moderated by: Bruce Clurman, MD, PhD

Featuring all speakers from session 4, afternoon keynote speaker + audience 

03:35 p.m. - 03:55 p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center