Targeting Transcription Factors

Novel Approaches to Modulate Seemingly Undruggable Targets

APRIL 10, 2023 | 1:00PM-5:15PM PDT

Transcription factors are proteins with DNA-binding domains that are involved in transcribing DNA into RNA. They are key cell regulators and alterations in their structure, binding or activity are often found associated with many abnormalities in cellular function or disease. Transcription factors have been targeted in different ways, by modulating their binding, interactions, activity, or expression levels, to generate the desired biological outcomes. However, their lack of defined structure and binding pockets have made them somewhat “undruggable”. This symposium on Targeting Transcription Factors brings together scientists who are working on innovative chemistries and technologies to target different transcription factors for therapeutic intervention.

Monday, April 10

Pre-Conference Symposium Registration Open (Indigo West Foyer)12:00 pm

Welcome Remarks1:00 pm

1:10 pm

Chairperson's Remarks

Erica Jackson, PhD, Executive Vice President, Target Biology, Scorpion Therapeutics

1:15 pm

Novel Tools and Strategies for Transcription Factor Drug Discovery

Erica Jackson, PhD, Executive Vice President, Target Biology, Scorpion Therapeutics

Transcription factors (TFs) are critical cancer drivers making them compelling targets for small molecule inhibition. The use of chemical proteomics to screen covalent small molecule libraries in live cells has enabled the identification of compounds that bind in previously unrecognized pockets on TFs. Creative approaches to developing biophysical and functional assays can overcome the challenges of working with recombinant TF proteins and provide a path toward drugging these important targets.

1:45 pm

Potent, Orally-Bioavailable, Efficacious TEAD Inhibitors

Stephen Gwaltney, PhD, Head, Drug Discovery, SpringWorks Therapeutics

Activity of the YAP/TAZ-TEAD complex represents a compelling pharmacologic target. We have identified novel small molecules that bind to the TEAD auto-palmitoylation pocket and these compounds are highly potent, orally bioavailable, and active against multiple cancer cell lines. In vivo models of Hippo pathway-altered xenografts showed that our inhibitors deliver consistent monotherapy activity, with dose-dependent and durable tumor regressions achieved at well-tolerated doses.

2:15 pm

FEATURED PRESENTATION: Targeting the Transcription Factor MYC through WDR5

Stephen W. Fesik, PhD, Professor of Biochemistry, Pharmacology, & Chemistry; Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University

One third of all cancer deaths in the United States are attributable to over-expression or activity of the transcription factor MYC. WD repeat domain 5 (WDR5) is a cofactor of MYC that is required for localizing WDR5 and MYC to chromatin. Rather than targeting MYC directly, we have discovered potent WDR5 inhibitors which disrupt MYC’s function and show promising activity in a variety of tumors.

Networking Refreshment Break2:45 pm

3:15 pm

PLX-4107, A Selective IKZF2 Degrader, Reprograms Suppressive Regulatory T Cells in Solid Tumors

Peggy Thompson, PhD, Vice President and Head of Biology, Plexium, Inc.

The transcription factor IKZF2 is required for maintaining stable Tregs. Depletion of IKZF2 converts Tregs into effector-T cells and loss of suppressive activity. Protein degradation enables targeting undruggable proteins without known ligand binding-sites (i.e. IKZF2). PLX-4107 was designed to induce a novel interaction between IKZF2 and the E3 Cereblon promoting protein degradation. PLX-4107 selectively degrades IKZF2 resulting in Treg conversion into effector-like T cells, antitumor activity and enhanced immune checkpoint therapy efficacy.

3:45 pm

FEATURED PRESENTATION: Reimagining Druggability Using Chemoproteomic Platforms

Daniel Nomura, PhD, Professor of Chemistry, Molecular and Cell Biology, Nutritional Sciences and Toxicology, University of California, Berkeley

We currently have three major research directions. One is developing and applying chemoproteomics-enabled covalent ligand discovery approaches to rapidly discover small-molecule therapeutic leads that target unique and novel ligandable hotspots for undruggable protein targets and pathways. Second focus is on using chemoproteomic platforms to expand the scope of targeted protein degradation technologies. Our third area focuses on using chemoproteomics-enabled covalent ligand discovery platforms to develop new induced proximity-based therapeutic modalities. This talk will focus on using covalent chemoproteomic strategies for drugging undruggable oncogenic transcription factors and also developing new induced proximity-based therapeutic modalities beyond degradation.

In-Person Group Discussion4:15 pm

In-Person Group Discussions are informal, moderated discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each discussion will be led by a facilitator who keeps the discussion on track and the group engaged. To get the most out of this format, please come prepared to share examples from your work, be a part of a collective, problem-solving session, and participate in active idea sharing. Please visit the In-Person Group Discussions page on the conference website for a complete listing of topics and descriptions.

IN-PERSON GROUP DISCUSSION:

Emerging Covalent and Degradation Strategies for Difficult Drug Targets

Daniel A. Erlanson, PhD, Senior Vice President, Innovation and Discovery, Frontier Medicines Corporation

Close of Symposium5:00 pm

Dinner Short Course Registration (Indigo West Foyer)5:00 pm

Dinner Short Courses*6:00 pm

*Premium Pricing or separate registration required. See Short Courses page for details.