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. We discover that 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. - 08:55 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, I will present some of our research in the development of highly potent and effective degraders and non-degraders to target transcriptional factors.          

08:55 a.m. - 09:15 a.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

TBD

Talk description to follow.

09:15 a.m. - 09:25 a.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Moderated by: Champak Chatterjee, PhD

Featuring all speakers from session 1 + audience

09:25 a.m. - 09:40 a.m. 

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Refreshments Available

09:40 a.m. - 09:55 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.

09:55 a.m. - 10:15 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. 

10:15 a.m. - 10:35 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.

10:35 a.m. - 10:55 a.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

TBD

Talk description to follow

10:55 a.m. - 11:30 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

11:50 a.m. - 12:30 p.m.

High-throughput mechanistic profiling of protein–small molecule interactions

Talk description to follow.

12:30 p.m. - 12:50 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.

12:50 p.m. - 01:10 p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

TBD

Talk description to follow.

01:10 p.m. - 01:20 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. The Institute of Protein Design developed 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. They validate potent, selective modulators with biochemical assays and structural analysis and show rapid redesign to generate Src-targeted inhibitors.

01:20 p.m. - 01:30 p.m.

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Moderated by: Alice Berger, PhD

Featuring speakers from session 3 + audience

01:30 p.m. - 01:50 p.m. 

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Refreshments Available

01:50 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

Talk description to follow. 

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

Pelton Auditorium, Weintraub Building
Fred Hutch Cancer Center

Co-opting the ubiquitin system for therapeutic benefit

Talk description to follow.

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