Biological Chemistry seminar, Jake Jaffe, Broad Institute

March 28, 2019 - 03:00 PM - 04:00 PM
Speaker: 

Jacob D. Jaffe

The Broad Institute

 

Lauren Rachel Zeitels Memorial Lecture

BIOLOGICAL CHEMISTRY SEMINAR

 

 

"Proteomic Connectivity Maps for Characterization and Targeting of Drugs" 

 

There has been an explosion of drug development in the kinase inhibitor and epigenetic modulator spaces.  The primary effects of both classes are fundamentally proteomic, altering the landscape of post-translational modifications in cells.  Mass spectrometry-based proteomic assays are uniquely suited to report on the molecular effects of these drugs. We have developed two scalable proteomic assays to this end: the P100 sentinel assay, which broadly reports on a wide range of signaling activities by monitoring a reduced-representation of the phosphoproteome, and the Global Chromatin Profiling assay, which monitors nearly all of the combinations and permutations of histone modifications commonly present in cells.  We generated a first-of-its-kind systematic library resource of proteomic drug signatures in cells. The majority of drugs generated reproducible signatures, but our analyses indicate the difficulty of identifying traditional “biomarkers” of activity that are paradigmatic for drug development. Eschewing biomarkers, we compared signatures using the "connectivity" concept, enabling data integration across cell types and assays, and co-integration of transcriptional signatures. Connectivity among cell types revealed cellular responses that transcended lineage, while connectivity agreement among assays revealed unexpected associations between drugs.  We further leveraged the resource against public data to recognize therapeutic hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. 

 

 

 

Thursday, March 28, 2019

3:00 PM

 

Carolyn Hoff Lynch Lecture Hall

 

Host:  Dr. David Christianson

Department of Chemistry

231 S. 34 Street, Philadelphia, PA 19104-6323

215.898.8317 voice | 215.573.2112 fax | web@chem.upenn.edu