Cambridge Healthtech Institute’s 6th Annual

Chemical Biology and Target Validation

The Design, Synthesis and Application of Chemical Probe Libraries for Target Engagement, Activity and Druggability Profiling

June 18-19, 2019

Advances in the development of highly-specific chemical probes, proteomics and quantitative mass spectrometry techniques, in conjunction with improved structural biology, are accelerating target identification, occupation and engagement studies. Yet mode of action deconvolution involving novel targets and probes, where only limited selectivity profiling has been carried out, still presents a significant challenge. The difficulty of this task is compounded further in the burgeoning field of protein degradation, where there exists an abundance of new chemical modalities. Cambridge Healthtech Institute’s Chemical Biology and Target Validation conference will bring together chemical biologists, medicinal and synthetic chemists, and drug discovery leaders from both academia and industry alike to discuss emerging tools and techniques that will determine best practices on how we can elucidate drug-target relationships even for the most novel of targets.

Final Agenda

Tuesday, June 18

7:00 am Registration Open and Morning Coffee

Harborview 3

8:00 Chairperson’s Remarks

Amanda L. Garner, PhD, Assistant Professor, Medicinal Chemistry, University of Michigan

8:10 Targeted Protein Degradation in Target Validation and Drug Discovery

Fisher_StewartStewart L. Fisher, PhD, CSO, C4 Therapeutics

Harnessing the ubiquitin proteasome system through heterobifunctional molecules for targeted protein degradation has the potential to transform drug discovery, both in the assessment of novel targets and the discovery of high impact therapeutics. This talk will discuss the development of target validation platform using this approach, as well as the fundamental concepts underpinning optimization of degrader therapeutics including understanding the importance of binding and kinetics in conjunction with thermodynamics.

8:40 FEATURED PRESENTATION: Targeting Unligandable Proteins for Degradation with Low Molecular Weight Cereblon Modulators

Chamberlain_PhilipPhilip Chamberlain, DPhil, Senior Director, Structural and Chemical Biology, Celgene

The clinically approved cereblon modulators thalidomide, lenalidomide and pomalidomide function by redirecting the CRL4-CRBN E3 ubiquitin ligase complex to cause proteasomal degradation of target proteins. Through this mechanism, ‘undruggable’ proteins can be targeted such as transcription factors. This presentation will discuss the phenotypic discovery of cereblon modulators with new therapeutic mechanisms, and describe how knowledge of the structural mechanism is informing the discovery of next generation therapeutics.

9:10 Principles of Small Molecule Mediated Ubiquitin Ligase Targeting

Fischer_EricEric S Fischer, PhD, Assistant Professor of BCMP, Cancer Biology, BCMP, Dana-Farber Cancer Institute, Harvard Medical School

Small molecules that induce protein degradation through ligase-mediated ubiquitination, have shown considerable promise as a new pharmacological modality. Thalidomide and related IMiDs provided the clinical proof of concept, while significant progress has recently been made towards chemically induced targeted protein degradation using heterobifunctional small molecule ligands. We will present recent work towards a better understanding of the molecular principles that govern neo-substrate recruitment, and other small molecule degraders.

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing


10:25 Design and Utilization of the Kinase Chemogenomic Set (KCGS) for Target Identification

Drewry_DavidDavid H. Drewry, PhD, Research Associate Professor, SGC-UNC, Eshelman School of Pharmacy, UNC Chapel Hill

We are building a kinase chemogenomic set (KCGS) in order to facilitate identification of kinases that play critical roles in disease. When complete, the set will contain narrow spectrum kinase inhibitors that inhibit each human kinase. Each kinase will be inhibited by at least 3 scaffolds, anticipating that different structures will have distinct off-target profiles. In this talk I will share details on the current set and its utility.

10:55 Identification of Kinase-Targeted Drug Combinations Using Chemoproteomics

Amanda GarnerAmanda L. Garner, PhD, Assistant Professor, Medicinal Chemistry, University of Michigan

This talk will describe the development of a chemoproteomic pipeline for identifying high-confidence kinase-substrate interactions with phosphosite specificity. Application of this methodology toward the discovery of new kinase-targeted drug combinations in cancer will be discussed.

Omicscouts 11:25 Target Fishing & Turnover, Lead Optimization & Drug Signalling, by Chemical Proteomics

Andreas KoepkeAndreas Koepke, Managing Director, BD OmicScouts

Concept_Life_Sciences 11:40 Development of a Specific Wee-1 Inhibitor

Scott_AndrewAndrew Scott, Head, Bioassay Development and Screening, Screening and Assay Development, Concept Life Sciences

Using a structure-based drug design approach, we exploited subtle active site differences to identify novel, potent WEE1 inhibitors that display high selectivity over PLK1. These compounds allowed us to demonstrate the distinct effects of WEE1 and PLK1 inhibition on cellular toxicity and confirm that adavosertib’s single agent efficacy is unlikely to be mediated solely through the inhibition of WEE1.

11:55 Transition to Lunch

12:00 pm Enjoy Lunch on Your Own

12:30 Session Break


1:05 Chairperson’s Remarks

Amanda L. Garner, PhD, Assistant Professor, Medicinal Chemistry, University of Michigan

1:10 Controlling Protein Homeostasis Using Chemical Probes

Jones_LynLyn H. Jones, PhD, Vice President, Chemistry and Chemical Biology, Jnana Therapeutics

Elucidation of the mechanisms of proteostasis will reveal new opportunities to pharmacologically regulate therapeutic targets. The utility of chemical probes to explore these new avenues for drug discovery will be presented.


1:40 Biochemical and Genetic Strategies for Small Molecule Target Identification

Nijhawan_DeepakDeepak Nijhawan, MD, PhD, Assistant Professor, Biochemistry and Oncology, UT Southwestern Medical Center

Cell based phenotypic screens for anti-cancer compounds have the potential to define new drug targets. Target identification for anti-cancer compounds is a prerequisite for drug development and remains technically challenging. We have used both forward genetics and click-chemistry for target identification. These efforts have unveiled either new drug targets or novel chemical scaffolds for existing drug targets.

2:10 Discovery of Allosteric Inhibitors of Beta-Catenin for Colon Cancer

Elmar_NurmemmedovElmar Nurmemmedov, PhD, MBA, Principal Investigator of Translational Neuroscience and Neurotherapeutics, Director of Drug Discovery, John Wayne Cancer Institute, Providence St. John’s Health

β-catenin is an attractive drug target due to its role in maintenance of cancer stem cells and potential to eliminate cancer relapse. We have identified C2, a novel β-catenin inhibitor, which is a small molecule that binds to a novel allosteric site on the surface of β-catenin. C2 selectively inhibits β-catenin, lowers its cellular load and significantly reduces viability of β-catenin-driven cancer cells. Through direct binding to β-catenin, C2 renders the target inactive that eventually activates proteasome system for its removal. Here we report a novel pharmacologic approach for selective inhibition of β-catenin via targeting a cryptic allosteric modulation site. Our findings may provide a new perspective for therapeutic targeting of β-catenin.

2:25 Refreshment Break in the Exhibit Hall with Poster Viewing

2:30-2:45 Speed Networking: Young Professionals


3:10 Phenotypic Screening and Target Identification in the Beta Cell

Wagner_BridgetBridget K Wagner, PhD, Institute Scientist, Chemical Biology and Therapeutics Science Program, Broad Institute

Small molecules that promote pancreatic beta-cell viability/function could have an enormous impact on diabetes as a disease-modifying therapy. Phenotypic approaches have been useful for identifying new intracellular targets, by allowing cells to reveal the most efficacious targets for desired phenotypes. Another key step is determining the mechanism of action for these compounds. Here, I will discuss how we are identifying small molecules that promote beta-cell regeneration, viability, and function.

3:40 A Chemical Approach to Map Protein Interactions at the Cell Surface

Hett_ErikErik Hett, PhD, Head, Experimental and Chemical Biology, Merck

Membrane proteins play key roles in recognition, communication, and signal transduction. We have developed both enzyme-based and small molecule-based approaches to label proteins in proximity to proteins of interest on living cells. This novel technology has been applied to different protein targets and cell types with the goal of identifying proteins of biological importance relevant to drug discovery.

4:10 Transition to Keynote


5:20 Taste of New England Welcome Reception in the Exhibit Hall with Poster Viewing

5:25 Meet the Plenary Keynotes

6:25 Find Your Table, Meet Your Moderator

6:30 Breakout Discussion Groups

7:30 Close of Day

Wednesday, June 19

7:00 am Registration Open and Morning Coffee

Harborview 3

8:00 Chairperson’s Remarks

Christopher W. am Ende, PhD, Senior Principal Scientist, Internal Medicine, Pfizer Inc.

8:05 Chemical Biology in Epigenetic and Epitranscriptomic Drug Discovery

Copeland_RobertRobert A. Copeland, PhD, Founder, President & CSO, Accent Therapeutics, Inc.

Epigenetic control of gene transcription and epitranscriptomic control of translation are critical mechanisms that help define cell differentiation and fate decisions. Both mechanisms involve enzyme-catalyzed covalent modifications of chromatin and RNA, respectively. Many cancers show critical and unique dependencies on the activity of specific epigenetic or epitranscriptomic enzymes. Examples of disease-associated enzymes and efforts to identify small molecule inhibitors against these enzymes as a therapeutic modality.

8:35 Application of Chemical Biology Probes in Drug Discovery

Johnson_DouglasDouglas Johnson, PhD, Director, Chemical Biology & Proteomics, Biogen

This talk will describe how we utilized clickable chemical biology probes for (off)-target identification, selectivity profiling and target engagement for multiple projects in Neuroscience drug discovery. Clickable probes of covalent inhibitors for targets such as FAAH and XPO1 will be discussed. In addition, clickable photoaffinity probes for gamma-secretase and BACE1 will be described.

Biognosys 9:05 Development of Limited Proteolysis Coupled to Mass Spectrometry, a Novel Drug Target Deconvolution Strategy

Yuehan FengYuehan Feng, PhD, Biognosys AG

Identification of drug targets and off-targets is central to both target-based and phenotypic drug discovery. We present a novel approach combining limited proteolysis and next-generation quantitative proteomics that enables unbiased profiling of compound-protein interactions in complex proteomes while also providing binding site prediction/confirmation.

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

10:05 Poster Winner Announced


10:20 Chemical Probes – Re-Thinking the Ecosystem

Kostic_MilkaMilka Kostic, PhD, Program Director, Chemical Biology, Department of Cancer Biology, Dana-Farber Cancer Institute

Chemical probes are research tools that can be used to interrogate intricate biological and preclinical questions. Although standards have emerged, their wide adoption, implementation and enforcement are lagging behind. In practice, many biologists continue to use discredited chemical probes, thus generating unreliable results. The talk will focus on some of the big picture questions surrounding chemical probes, their use and standards, and present ways to address current challenges.

10:50 Chemical Biology Influencing Drug Discovery

am_Ende_ChristopherChristopher W. am Ende, PhD, Senior Principal Scientist, Internal Medicine, Pfizer Inc.

Chemical biology has broad influence on many drug discovery programs. This presentation will highlight several vignettes across different projects including the development of biotinylated cleavable-linker photoprobes to evaluate inhibitor interaction with γ-secretase, profiling the covalent adduct stability of irreversible MAGL inhibitors and the identification of off-targets of BACE inhibitors using clickable photoaffinity probes.

11:20 Building Knowledge from Chemical and Biological Signatures

Lounkine_EugenEugen Lounkine, PhD, Senior Investigator I, Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research

Biological signatures of compounds and diseases have become commonplace, including historical observations in high-throughput assays, high-content imaging, and gene expression signatures. How do we capitalize on that data, as well as the rich, yet unstructured information in biomedical literature? Our group places signatures at the center of our data – their similarity and clustering play a pivotal role in target identification, hypothesis-driven compound library design, virtual screening, and target deconvolution.

11:50 Transition to Lunch

12:00 pm Enjoy Lunch on Your Own

12:30 Transition to Plenary


2:20 Booth Crawl and Dessert Break in the Exhibit Hall with Poster Viewing

2:25 Meet the Plenary Keynotes

3:05 Close of Conference

Stay on to attend Wednesday, June 19 - Thursday, June 20

Target Identification & Phenotypic Screening

Recommended Short Courses

SC1: Introduction of GPCR-Based Drug Discovery
SC6: Targeted Protein Degradation Using PROTACs and Molecular Glues