Cambridge Healthtech Institute’s Inaugural

Targeting Transcription Factors

Innovative Chemistries, Assays, and Modalities for Increasing Druggability

September 27 - 28, 2023 EDT

Transcription factors are proteins with DNA-binding domains that are involved in gene transcription. They are key cell regulators and alterations in their structure, binding, or activity are often found associated with many abnormalities in cellular function and in 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.” Cambridge Healthtech Institute’s conference on Targeting Transcription Factors brings together scientists who are working on innovative ways to help modulate various transcription factors for therapeutic intervention.

Wednesday, September 27

PLENARY KEYNOTE PROGRAM

10:40 am

Plenary Chairperson’s Remarks

An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech Institute

10:45 am

PLENARY: The New Science of Therapeutics

Jay E. Bradner, MD, Physician Scientist, Former President, Novartis Institutes for BioMedical Research, Inc.

I will share reflections on how new paradigms in the science of therapeutics are creating opportunities to approach historic challenges in medicine. Specifically, I will share approaches to targeting transcription factors and discuss how modularity is a paradigm for next-generation low-molecular weight and biological therapeutics. Finally, I will offer reflections on drug development and the fitness, opportunities, and challenges of the biomedical ecosystem.

11:30 am

PLENARY: Accelerating Drug Discovery Using Machine Learning and Cell Painting Images

Anne E. Carpenter, PhD, Senior Director, Imaging Platform & Institute Scientist, Broad Institute

Shantanu Singh, PhD, Senior Group Leader, Machine Learning, Imaging Platform, Broad Institute

Microscopy images can reveal whether a cell is diseased, is responding to a drug treatment, or whether a pathway has been disrupted by a genetic mutation. In a strategy called image-based profiling, often using the Cell Painting assay, we extract hundreds of features of cells from images. Just like transcriptional profiling, the similarities and differences in the patterns of extracted features reveal connections among diseases, drugs, and genes.

Enjoy Lunch on Your Own12:15 pm

Welcome Remarks1:45 pm

TRANSCRIPTION FACTOR-DRIVEN TARGETED THERAPIES

1:50 pm

Chairperson's Remarks

Lindsay Pino, PhD, CTO and Co-Founder, Talus Bioscience

1:55 pm FEATURED PRESENTATION:

Mammalian SWI/SNF Chromatin Remodeling Complex- Transcription Factor Interactions in Human Cancer

Cigall Kadoch, PhD, Associate Professor, Pediatric Oncology, Dana-Farber Cancer Institute/Harvard Medical School; Scientific Founder, Foghorn Therapeutics

ATP-dependent chromatin remodeling complexes are heterogeneous, multi-component molecular machines that govern genomic accessibility and gene expression and are frequently perturbed in human disease. This presentation highlights biochemical and structural advances that have enabled the mechanistic understanding of mSWI/SNF complex activities and functional assignment of mSWI/SNF-transcription factor interactions in developmental and disease states, opening new opportunities for targeted intervention.

2:55 pm “Le Pas de Deux” — Uncovering Protein-Protein Interaction Assays for Transcription Factors

Daniela Crespi, PhD, Principal Investigator Proposal, Biological Sciences Department, Axxam

Transcription factors represent key biological players in multiple signaling pathways within eukaryotic cells. It is therefore not surprising that their dysregulation contributes to the pathogenesis of a plethora of human diseases, including cancer, making them highly attractive for therapeutic intervention.  Axxam has developed several cell-free and cell-based assays for therapeutically relevant transcription factors, aiming at finding meaningful modulators that can be further developed into lead candidates.

Refreshment Break in the Exhibit Hall with Poster Viewing3:25 pm

4:05 pm

A Transcription Factor Atlas of Directed Differentiation

Julia Joung, PhD, Postdoctoral Fellow, Laboratory of Dr. Jonathan Weissman, Whitehead Institute

To comprehensively understand transcription factors (TFs), we created a barcoded library of all human TF splice isoforms and applied it to build a TF Atlas charting single-cell expression profiles of pluripotent stem cells overexpressing each TF. We validated TFs for generation of diverse cell types, spanning all three germ layers and trophoblasts. We further developed a strategy for predicting TF combinations that produce target cell types to accelerate cellular engineering.

4:35 pm

Synthetic Transcription-Factor Activity Responsive (STAR) Gene Circuits for Cancer Immunotherapy

Ming-Ru Wu, MD, PhD, Assistant Professor, Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School

We have developed synthetic cancer-targeting gene circuits that specifically target cancer cells. Once the circuits enter cells, they will sense the activity of several cancer-associated transcription factors and get activated in tumor cells to trigger tumor-localized combinatorial immunotherapy. Circuits mediate robust therapeutic efficacy in ovarian cancer mouse models. This platform can be adjusted to treat multiple cancer types and can potentially trigger genetically encodable immunomodulators as therapeutic outputs.

Dinner Short Course Registration*5:00 pm

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

Diversity Discussion (Sponsorship Opportunity Available)5:05 pm

IN-PERSON GROUP DISCUSSION:

Embracing All Shades of Diversity

Stephanie Ashenden, PhD, Senior Informatician, Artificial Intelligence & Machine Learning, AstraZeneca

Dele Babalola, Senior Director, Clinical Data Management, Morphic Therapeutic

Saudat Fadeyi, PhD, MBA, Director, Business Development, Ovid Therapeutics

Rabia Khan, PhD, MBA, CEO, Serna Bio

Daniel La, PhD, Vice President & Head, Medicinal Chemistry, Triana Biomedicines, Inc.

Joel Omage, Research Scientist II, CVM Disease Area, Novartis Institutes for Biomedical Research, Inc.

Join us for this interactive, informal, candid 55-minute discussion on welcoming and increasing all aspects of diversity in the life sciences. We have invited some engaging speakers to share their stories and experiences on initiatives that have and haven’t worked. Our goal is to help the audience learn, question, and get motivated to improve diversity in their own environments. This discussion will not be recorded nor available for on-demand access.

Topics for discussion will include, but certainly not be limited to: 

  • Importance of fostering empathy 
  • Recognizing and supporting neurodiversity
  • Encouraging and implementing diversity in thought
  • Creating avenues for improving gender diversity and participation
  • Increasing racial diversity, particularly in leadership positions
  • Reaching low income and underprivileged neighborhoods to eliminate any “zipcode bias”
  • Understanding and addressing other hidden barriers and biases
  • Implementing mentorship and internship programs that are simple yet impactful​​

Close of Day8:00 pm

Thursday, September 28

Registration and Morning Coffee7:30 am

TRANSCRIPTION FACTORS AS DRUG TARGETS

8:00 am

Chairperson's Remarks

Asad Taherbhoy, PhD, Director, Drug Discovery, Foghorn Therapeutics

8:05 am

Targeting CBP/p300 – Inhibition vs. Degradation for Potent Anti-Tumor Efficacy

Kavitha Nellore, PhD, Senior Director, Cell & Molecular Biology, Aurigene Oncology

E1A binding protein (p300) and its paralog CREB binding protein (CBP or CREBBP) are key transcriptional co-activators that play a critical role in gene expression in both tumor and immune cells. Our efforts in understanding the distinct advantages of inhibition vs. degradation of CBP/p300 for use in cancer therapy resulting from a combination of synthetic lethality, inhibition of pro-tumorigenic signaling, and activation of anti-tumor immune response will be presented.

8:35 am

Targeting MYC Through WDR5

William Tansey, PhD, Ingram Professor of Cancer Research, Professor of Cell & Development Biology, Vanderbilt University

MYC proteins are highly validated but challenging targets for cancer therapy. In this talk, I will describe our efforts—in collaboration with Dr. Stephen Fesik—to target MYC via its chromatin cofactor WDR5. These efforts, now nearing completion, have generated highly potent, orally bioavailable, and safe drug-like WDR5 inhibitors that stymie the ability of MYC to promote protein synthesis and display anti-tumor activity in multiple MYC-driven cancer models.

9:05 am

Profiling the DNA Regulome to Discover Direct Inhibitors of the Brachyury Transcription Factor

Lindsay Pino, PhD, CTO and Co-Founder, Talus Bioscience

TF-Scan is a live-cell assay that reports the proteome-wide changes in protein:DNA binding activity in response to small molecule perturbations. Using this technology, we discovered covalent compounds capable of binding and disrupting the activity of brachyury, a previously undruggable TF that drives sarcoma. Hit validation and medicinal chemistry led to a covalent chemical probe for brachyury, effective in chordoma cell line models with in vivo activity against patient-derived xenografts.

9:35 am

FEATURED PRESENTATION: Elucidating the MOA of Allosteric Lipid Pocket Inhibitors of TEAD

Debra Brennan, Executive Director, Medicinal Chemistry, Nimbus Therapeutics

At Nimbus, we have overcome the challenges of TEAD’s central lipid pocket to develop a robust biochemical assay and have used structural elucidation and computational chemistry, along with in-parallel orthogonal approaches to understand the mechanism-of-action (MOA) of small molecule inhibitors of TEADs. Our work uncovers different MOAs of TEAD small molecule inhibitors and provides hypotheses for these MOAs which could help the discovery of more potent and selective inhibitors.

In-Person Group Discussions10:05 am

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 3B:

Challenges and Opportunities in Pursuing Transcription Factors

Debra Brennan, Executive Director, Medicinal Chemistry, Nimbus Therapeutics

Rhushikesh Kulkarni, PhD, Principal Scientist, Oncology Chemical Biology, Pfizer Inc.

Asad Taherbhoy, PhD, Director, Drug Discovery, Foghorn Therapeutics

William Tansey, PhD, Ingram Professor of Cancer Research, Professor of Cell & Development Biology, Vanderbilt University

  • Assays and screening strategies to identify modulators of transcription factors 
  • Structural and mechanistic approaches for understanding mechanism of action
  • Emerging transcription factors as viable drug targets for the various indications
  • Designing potent, orally bioavailable drugs that target co-activators and inhibitors 
  • Pursuing degradation as a therapeutic strategy for targeting transcription factors​

Coffee Break in the Exhibit Hall with Poster Viewing10:50 am

11:30 am

HT-CETSA for Transcription Factor Ligand Discovery

Rhushikesh Kulkarni, PhD, Principal Scientist, Oncology Chemical Biology, Pfizer Inc.

High-throughput CETSA (HT-CETSA) is a promising screening strategy for identifying target binders in the native cellular environment. We have performed HT-CETSA screening to enable chemical engagement of transcription factors. Here we will discuss key learnings from our HT-CETSA screening efforts.

12:00 pm

NX-2127:  A Degrader of BTK and IKZF1/3

Davorka Messmer, PhD, Senior Director, Discovery Biology, Nurix Therapeutics

I describe preclinical and clinical data for NX2127, a degrader of Bruton Tyrosine Kinase (BTK), a master regulator of B cells and implicated in cancer. We developed two unique and functionally distinct BTK degraders that harness cereblon (CRBN), an E3 ligase active in hematopoietic cells. I describe the BTK degrader that also has the ability to induce degradation of neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3).

Enjoy Lunch on Your Own12:30 pm

Dessert Break in the Exhibit Hall with Last Chance for Poster Viewing1:35 pm

DEGRADING ONCOGENIC TRANSCRIPTION FACTORS

2:15 pm

Chairperson's Remarks

Charles Wartchow, PhD, Associate Director, Global Discovery Chemistry, Novartis Institutes for BioMedical Research

2:20 pm

Understanding the Recruitment of Zinc-Finger-Based Transcription Factors to Cereblon in the Presence of Molecular Glues

Charles Wartchow, PhD, Associate Director, Global Discovery Chemistry, Novartis Institutes for BioMedical Research

Transcription factors are known to bind to cereblon in the presence of molecular glues and some reports implicate interactions with multiple zinc fingers. We present biophysical and structural assessments of the minimal binding domains of IKZF2 and another transcription factor revealing that two zinc fingers interact with cereblon:glue complexes. In these examples, the binding modes are distinct and may have implications for the design of selective degraders.

2:50 pm

Discovery and Characterization of an IKZF2 Selective Molecular Glue Degrader with Best-in-Class Potential

Courtney Havens, PhD, Director of Biology, Proteovant Therapeutics, Inc.

IKZF2 (Helios) plays an important role in maintaining stability and function of regulatory T cells (Tregs). Proteovant applied a structure-guided drug discovery approach to identify an IKZF2 selective molecular glue degrader, PVTX-405. PVTX-405 shows selective degradation of IKZF2 in vitro and in vivo. PVTX-405 treatment reduces suppressive activity of human Treg cells ex vivo and delays growth of MC38 tumors in immune competent mice in vivo.

3:20 pm

New Technologies for Advancing the Targeted Protein Degradation

H. Ümit Kaniskan, PhD, Associate Professor, Laboratory of Dr. Jian Jin, Department of Pharmacological Sciences, Icahn School of Medicine at Mt. Sinai

The Jian Jin Laboratory at Mount Sinai is a leader in discovering novel degraders targeting oncogenic proteins and developing new technologies for advancing the targeted protein degradation field. Our lab’s recent progress advancing the targeted protein degradation, including TF-PROTAC, Bridged PROTAC, Folate-caged PROTAC, opto-PROTAC, and KEAP1-recruiting PROTAC technologies will be presented.

3:50 pm

Targeted Degradation of STAT Proteins

Longchuan Bai, PhD, Associate Research Scientist, Laboratory of Dr. Shaomeng Wang, University of Michigan

STAT (signal transducer and activator of transcription) proteins are a family of transcription factors that mediate signal transduction downstream of cytokine and growth factor receptors. Hyperactivation of STAT3 and STAT5 has been linked to cancer cell proliferation, survival, stemness, and immune evasion, making them attractive targets for cancer therapy. STATs have been difficult to target by traditional small-molecule inhibitors. Employing the PROTAC technology, we have developed highly selective and potent STAT3 or STAT5 degraders with strong anti-tumor activities in hematologic cancer models.

Close of Conference4:20 pm