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Session I: Hosted by Dr. Carolyn Bertozzi [clear filter]
Monday, July 1

10:45am EDT

Attenuating Oncogenic Transcription with Small Molecules
The Koehler Lab uses chemical biology approaches to investigate deregulated transcriptional programs in cancer. We are taking on the challenge of developing chemical probes that either directly target oncogenic transcription factors (TFs), currently deemed ‘undruggable,’ or that target ‘nearest neighbor’ proteins that indirectly modulate TF function through mechanisms involving alterations in protein production or protein stability. The probes can be used to further understand the functions surrounding any given transcriptional regulator, clarify their relevance as therapeutic targets, and enable credentialing of mechanisms for targeting by small-molecule drugs. As an example of our approach, probes that impact the MYC oncogene, which encodes a master regulator and is causally associated with most human malignancies, will be described.  The lab identified a unique small molecule, KI-MS2-008, that binds to MAX, inhibits MYC-driven transcription, and stabilizes the MAX homodimer in vitroand in cells while reducing MYC protein levels. The compound displays anti-tumor activities in vitro and in vivo using engineered and non-engineered systems.

avatar for Angela Koehler, PhD

Angela Koehler, PhD

Associate Professor, Biological Engineering, MIT
Angela Koehler is the Goldblith Career Development Professor in Applied Biology in the Department of Biological Engineering at MIT and an intramural member of the David H. Koch Institute for Integrative Cancer Research at MIT. She is also an Institute Member of the Broad Institute... Read More →

Monday July 1, 2019 10:45am - 11:15am EDT
Abigail Adams Salon A/B

11:15am EDT

Turning up the Volume: Augmenting Natural 14-3-3/phosphoprotein Interactions
Scaffolding proteins act as protein-interaction hubs, but have been considered nearly un-targetable by drugs and chemical probes.  The seven human isoforms of 14-3-3 are ubiquitous mediators of kinase pathways, modulating the function, stability, and subcellular localization of phosphorylated client proteins. In collaboration with the Ottmann lab (Eindhoven University of Technology), we are using fragment-based ligand discovery and structure-guided design, to systematically develop molecules that stabilize specific 14-3-3/phosphopeptide complexes.  To date, we have discovered stabilizing fragments for five important cancer targets, and are designing more potent covalent and noncovalent compounds for testing in cells.  Our long-term goal is to use these molecular probes to dissect the 14-3-3 PPI network and validate targets for therapeutic intervention.

avatar for Michelle Arkin, PhD

Michelle Arkin, PhD

Professor, Pharmaceutical Chemistry, University of California, San Francisco
Michelle Arkin is a chemical biologist/biochemist interested in developing first-in-class modulators of really challenging targets, such as protein-protein interactions, transcription factors, and aggregating proteins. Her lab works on protein-protein interaction networks in cancer... Read More →

Monday July 1, 2019 11:15am - 11:45am EDT
Abigail Adams Salon A/B

11:45am EDT

Chemoproteomic technology for the direct identification of druggable protein nucleophiles
avatar for Jack Taunton, PhD

Jack Taunton, PhD

Professor, Cellular Molecular Pharmacology, University of California, San Francisco

Monday July 1, 2019 11:45am - 12:00pm EDT
Abigail Adams Salon A/B

12:00pm EDT

Using cell-based profiling to develop predictive signatures of toxic and intractable small molecules
Small-molecule profiling methods, such as cell painting gene expression analysis, can be very useful for uncovering mechanism of action for novel compounds and for identifying compound similarities. In this project, we aim to use such small-molecule profiling methods to develop signatures of bioactivity. Here, we have applied this approach to develop predictive signatures of drug candidates with in vivo toxicity, and of nuisance compounds that are often false-positives in high-throughput screening. In particular, we tested a set of ~400 thiol-reactive compounds in cell painting, and found that these compounds comprise an independent cluster by principal component analysis. We anticipate that this approach will provide an rapid and efficient route for uncovering complex phenotypes induced by small molecules.

avatar for Bridget Wagner, PhD

Bridget Wagner, PhD

Institute Scientist, Broad Institute
Bridget Wagner is an Institute Scientist in the Chemical Biology & Therapeutics Science (CBTS) Program at the Broad Institute. Her group focuses on the discovery of small molecules that beneficially impact pancreatic beta-cell biology (proliferation, survival, insulin secretion... Read More →

Monday July 1, 2019 12:00pm - 12:15pm EDT
Abigail Adams Salon A/B

12:15pm EDT

Discovery of small molecule binding site hotspots in the global proteome
All biological processes are governed by chemical signals relayed through protein networks. These small molecule signals can inhibit, enhance, or impart new functions to proteins through direct associations to allosteric regulatory hotspots on a protein that drive alteration of the broader proteomic network.  To discover allosteric hotspots in the global proteome, we developed a chemical proteomics platform termed small molecule interactome mapping by photo-affinity labeling (SIM-PAL).  SIM-PAL uses a small molecule carrying a photo-affinity label to capture molecular interactions within the global proteome.  After treatment of live cells with the small molecule, the resulting interactions are captured by photochemical conjugation.  The small molecule-conjugated proteome is tagged with a cleavable biotin azide probe by copper-mediated azide–alkyne cycloaddition (CuAAC) for affinity enrichment and isotope-recoding.  The enriched proteins are identified by proteomics and the exact binding sites are mapped by isotope-targeted mass spectrometry (MS). Isotope-targeted MS enables the selection of small molecule-linked peptides against a background of unlabeled peptides for high-confidence identification of the underlying molecular structure.  SIM-PAL combines phenotypic cellular assays with high-resolution structural measurement of where and when a small molecule is binding throughout the whole proteome using the discovery power of MS.  Applications of SIM-PAL to bioactive small molecules and the structural implications of binding site hotspots from photo-affinity labeling chemistry will be described.

avatar for Christina Woo, PhD

Christina Woo, PhD

Assistant Professor, Harvard University
Christina M. Woo is an assistant professor in the Department of Chemistry and Chemical Biology at Harvard University, and an affiliate member of the Broad Institute. She obtained a BA in Chemistry from Wellesley College (2008), and conducted undergraduate research in the laboratory... Read More →

Monday July 1, 2019 12:15pm - 12:30pm EDT
Abigail Adams Salon A/B