Cambridge Healthtech Institute's 7th Annual

Lead Generation Strategies

Small Molecule Drug Discovery Innovations

September 27 - 28, 2023 EDT

Cambridge Healthtech Institute’s annual Lead Generation Strategies conference illuminates the latest approaches used by medicinal, biophysical and computational chemists to discover and develop small molecules (and now slightly larger molecules that retain potential for oral bioavailability) into drug candidates. Join us to hear case studies applying orthogonal biophysical approaches and other methods such as DNA-encoded libraries (DEL) and fragment-based drug design (FBDD) to hit-finding against what were once considered undruggable targets. These newer tools have enabled screening against non-traditional intracellular drug targets such as protein or nucleic acid/protein complexes involving protein-protein interactions (PPIs) and enzymes with hard-to-reach catalytic sites.

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

LEAD GENERATION BEST PRACTICES

1:50 pm

Chairperson's Remarks

Gottfried Schroeder, PhD, Associate Principal Scientist, Quantitative Biosciences, Merck & Co., Inc.

1:55 pm

FEATURED PRESENTATION: A Small-Molecule Drug Discovery Analysis: Pairing Recent 'Hits' with Clinical Candidates 

Dean G. Brown, PhD, Vice President & Head, Chemistry, Jnana Therapeutics

An analysis of 156 recently published clinical candidates was conducted to identify lead generation strategies frequently leading to drug candidates. These were categorized by previously known compounds, random HTS, focused screening, FBLG, and DEL, and it was determined that most clinical candidates were derived from previously known examples (>50%). Changes in physical properties and Tanimoto similarities from hit-to-clinical candidate are discussed, as well as implications on hit generation strategies.

2:25 pm

The HAT in the KAT: PAINS Recognition Enables Breakthrough Discovery of KAT6A Inhibitors

Jonathan B. Baell, PhD, Executive Director, Early Leads Chemistry, Lyterian Therapeutics

In 2018 we published in Nature our discovery of KAT6A inhibitor WM-1119, with the ensuing KAT druggability validation thereby oxygenating an industry of KAT drug discovery. Widely unknown is that WM-1119 discovery was challenged early on by noisy and misleading sets of hits, PAINS, and otherwise nuisance compounds. Here we chronicle this rollercoaster journey and impart what we hope are useful lessons to others at the public-private compound library design and drug discovery interface.

2:55 pm Lead Discovery for Challenging Targets and Unusual Modes-of-Action using DNA-Encoded Chemistry

Matthew Clark, CEO, X-Chem, Inc.

X-Chem operates a DNA-Encoded Chemistry platform that permits the simultaneous screening of billions of small molecules for their ability to engage protein targets.  Examples will be presented that exemplify the use of this technology to discover progressible compounds with a wide range of modes-of-action including orthosteric and allosteric inhibitors, activators, bispecific degraders and glues for a wide range of target classes.  X-Chem can help you achieve your drug discovery goals.

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

4:05 pm

Best Practices and Novel Trends in High-Throughput Screening Campaigns

Sujatha Gopalakrishnan, Director, Research Fellow, Head of HTS & Molecular Characterization, AbbVie

Efficient processes and high-quality chemical matter at every step of early drug discovery are critical to generate cost-effective, efficacious preclinical candidates. At Abbvie, the HTS team implements optimal target-based biochemical and cellular screens, followed by hit triage processes to eliminate false positives and advance hits to lead optimization and beyond. This talk will focus on best practices and strategies for generation of leads through robust assays, counter screens, orthogonal assays, novel technologies, and streamlined workflows.

4:35 pm

Versatile Applications of Affinity Selection-Mass Spectrometry (ASMS) for Challenging Drug Targets

Hans-Peter N. Biemann, PhD, Distinguished Scientist, Integrated Drug Discovery, Sanofi

I discuss how credentialed ASMS platforms impact membrane protein, transcription factor, and cytokine PPI space. Examples will include rapid ID of series with SAR in Sanofi’s collection for a small G protein, and screening of a 400k library to generate a dozen attractive chemical scaffolds with potent inhibition of a peptide transporter. In case studies I will cover rationale for matching various modalities/workflows with early discovery-stage scenarios. 

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

COVALENT, AFFINITY AND PROXIMITY-BASED STRATEGIES

8:00 am

Chairperson's Remarks

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

8:05 am

Development of a Covalent Hit-Identification Platform to Unlock Undruggable Targets

Simon Lucas, PhD, Associate Principal Scientist, Medicinal Chemistry, AstraZeneca

As the drug-discovery industry focuses on increasingly difficult-to-drug targets, unlocking these through covalent modification can have a transformative effect on our perception of druggability. For targets without a well-defined binding site, an electrophile-first approach may be required to deliver tractable starting points where reversible hit finding had failed. This talk will focus on current best practice for covalent hit-identification at AstraZeneca, covering: screening platforms, library design, and hit validation.

8:35 am

Reverse Polarity Activity-Based Protein Profiling

Megan L. Matthews, PhD, Assistant Professor, Chemistry, University of Pennsylvania

The polar chemistry of activity-based protein profiling (ABPP) probes was reversed by deploying the nucleophilic hydrazine pharmacophore found in old CNS drugs to show organohydrazines are active-site-directed and mechanism-based inhibitors of protein classes that are difficult to drug. Using the first N-nucleophile fragment/probe library, we showed that potent and selective inhibitors can be developed and that reverse-polarity ABPP can advance small molecules that modulate diverse electrophile-dependent functions.

9:05 am

PDE Inhibitors with Isozyme Selectivity Discovered with DEL Screening

Douglas J. Marcotte, Director, Protein Science, Valo Health

PDEs represent a superfamily of enzymes that degrade cyclic nucleotides modulating numerous signaling pathways in normal and diseased states. Because of the breadth of PDE signaling, inhibitors with exquisite selectivity are desired to avoid off-target effects. We screened a family of homologous PDEs using a parallel DEL strategy, identified inhibitors with isozyme selectivity, determined novel PDE co-crystal structures, and began evaluating these inhibitors in cell-based assays.

9:35 am

Using a Macrocyclic Scaffold to Discover bRo5 yet in vivo Active Proximity-Induced Degraders 

Jakob Fuhrmann, PhD, Senior Principal Scientist, Peptide Therapeutics, Genentech, Inc.

The development of proximity-induced degraders into viable drug candidates still poses several challenges, including their relatively low cell permeability aswell as high degree of conformational flexibility due to the presence of flexible linker elements. I will present our strategy to identify conformationally constrained macrocyclic degraders. I will further delineate our lead generation approach, including ternary complex stabilization as well as property-based optimizations to ultimately achieve target degradation in vitro and in vivo.

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 6B1: DNA-Encoded Libraries (DELs) for Lead Discovery

Rachael Jetson, PhD, Senior Director, Lead Discovery, Valo Health

Douglas J. Marcotte, Director, Protein Science, Valo Health

  • Protein quality in DEL; what have we learned?
  • Moving into the perceived ‘unDELable’ targets (RNAs, GPCRs, cellular, etc.); what are the current advances/thoughts?
  • Making the most of your DEL platform by focusing on library design and selection conditions​

IN-PERSON GROUP DISCUSSION 6B2: Innovations in Biophysical Tools

Gottfried Schroeder, PhD, Associate Principal Scientist, Quantitative Biosciences, Merck & Co., Inc.

Phillip Schwartz, PhD, Director, Biophysics, Septerna

  • Application of orthogonal approaches 
  • New biophysical tools (ASMS and more) 
  • Integrating info from FBDD, DEL, HTS campaigns​

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

INTEGRATED STRATEGIES FOR LEAD GENERATION

11:30 am

Integrating HTS and DEL Hits in the Lead Generation and Optimization of PLD2 Inhibitors

Hasan Khan, PhD, Senior Scientist II, Global Medicinal Chemistry, AbbVie, Inc.

Murine in vivo studies have shown that PLD2 deficiency significantly reduced psoriasiform inflammation in IL-23-injected ears. Efficient and PLD2-selective hits from a high-throughput screen were identified and modified to improve potency and pharmacokinetic attributes. Structural features from hits identified in a DNA-encoded library screen were studied using in silico modeling and incorporated to improve binding kinetics. These efforts culminated in the identification of efficient in vivo active PLD2 inhibitors.

12:00 pm

Cells, DELs, and Gels: Next-Gen Encoded Library Screening 

Brian M. Paegel, PhD, Professor, Pharmaceuticals Sciences, University of California, Irvine

I provide updates on activity-based DEL technology, which interfaces solid-phase “OBOC” libraries with HTS-style activity assay. Our recent efforts focus on three thematic areas: 1) the discovery of translation modulators as a general strategy for interrogating the proteome via one universal biochemical activity assay, 2) development of pharmacokinetic assays for analyzing “beyond Rule of 5” libraries, and 3) novel 3D tissue culture strategies to enable cell-based DEL screening.

12:30 pm DNA-Encoded Library Technology: Development and Application to Small Molecule Drug Discovery

Alex Shaginian, Vice President of Business Development and Chemical Sciences, HitGen

The DNA-Encoded Library (DEL) technology presents a disruptive hit identification platform that can vastly expedite the course of early-stage small molecule drug discovery. HitGen is a world leader in the development and practice of the DEL technology with over 500 DEL clients. I will describe various DEL platforms that have been built and established at HitGen and present several success stories.

Enjoy Lunch on Your Own1:00 pm

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

NEW METHODS FOR LEAD DISCOVERY

2:15 pm

Chairperson's Remarks

Xiangdong Xu, MS, Senior Scientist II, Global Medicinal Chemistry, AbbVie

2:20 pm

A Synthetic Biology Platform to Find Cryptic Pockets on Challenging Targets

Jerome M. Fox, PhD, CEO, Think Bioscience

The design of small molecules that modulate the activity of disease-relevant proteins represents a longstanding challenge of medicinal chemistry. I will describe an approach for encoding this challenge into a microbial host and using it to guide the discovery and biosynthesis of targeted, biologically active molecules. Our high-throughput method accesses novel chemical fragments that are well suited for finding new functional cryptic sites. I will discuss the case of PTP1B.

2:50 pm

RAPID: A Chemoproteomics Technology Enabling the Discovery of Reversible Binders to Targets in Living Cells

Matthew Labenski, PhD, Dir Proteomics & Chemical Biology, Proteomics & Chemical Biology, Jnana Therapeutics Inc

RAPID is a next-generation chemoproteomics technology for identifying small molecules that bind reversibly to a pre-specified target of interest in a living cell. We will introduce the RAPID assay technology and describe its application towards the discovery of first-in-class inhibitors of SLC6A19, a genetically validated target for the treatment of PKU, as well as the first described ligands for the transcription factor IRF3 for the treatment of interferon-driven autoimmune disease.

3:20 pm

Engineering Cells to Discover Functional Protein Interaction Modulators

Maria Soloveychik, PhD, Co-Founder & CEO, SyntheX

SyntheX built platforms to modulate protein interactions. ToRPPIDO discovers compounds that can disrupt a specific protein-protein interaction. ToRNeDO does the inverse and discovers molecular glues that bring a pre-specified E3 ubiquitin ligase and a neosubstrate of interest together to achieve targeted protein degradation. Using genetically engineered circuits, the platforms rely on intracellular drug selection—bypassing many of the bottlenecks that exist with canonical in vitro or computational screening approaches.

Close of Conference3:50 pm