DDLSS: Liron Bar-Peled "Identification of Druggable and Redox Vulnerabilities in Cancer"

Liron is the Rullo Family Endowed Chair for Cancer Research at MGH and an Associate Professor of Medicine in Biological and Biomedical Sciences at Harvard Medical School. He received his Bachelor of Science degree in Biochemistry from the University of Georgia and his PhD in Biology from the Massachusetts Institute of Technology, where he used advanced cellular and molecular techniques to uncover how nutrients are sensed. As a Damon Runyon Postdoctoral fellow at the Scripps Research Institute, he leveraged chemical proteomic technologies to understand how cancer cells respond to oxidative stress. Having started his lab at the Krantz Family Center for Cancer Research, he has made important contributions to understanding how tumors sense and respond to metabolic stress and identifies new druggable vulnerabilities by integrating technologies that leverage high-throughput biochemistry, chemistry, and analytics with clinical insights. Liron’s work led to the founding of Scorpion Therapeutics (acquired by Eli Lily) and he has been widely recognized in the field as a Pew-Stewart Scholar, Mark Foundation Emerging Leader Award, NIH/NCI Merit Award, V Foundation Scholar, MRA young investigator and Damon Runyon Innovator. Proteins that sense intracellular reactive metabolites and regulate their production play essential roles in coordinating pathways implicated in human diseases, including cancer and neurodegeneration. Using VPS35 as a model reactive oxygen species (ROS) sensor, I demonstrate that oxidation of key VPS35 cysteines disrupts Retromer association with endosomal membranes, triggers plasma membrane remodeling, and suppresses mitochondrial translation to limit ROS output. Building on the concept of targeted cysteine oxidation, we developed molecular COUPLrs—small molecules bearing two cysteine-reactive warheads—together with CONNECT, an integrated chemical proteomic platform for target deconvolution. Profiling a COUPLr library across 13 cancer cell lines revealed 118 protein classes that can be chemically coupled, including mutant-selective complexes. We further engineered an advanced COUPLr targeting the oncogenic fusion EML4–ALK, which engages the EML4 domain, perturbs protein dynamics, and disrupts downstream signaling. Notably, COUPLr binding promotes proteasome-mediated degradation of EML4–ALK, a feature shared with ALK-directed drugs converted into COUPLrs. Together, molecular COUPLrs offer an unbiased strategy to discover small molecules that selectively target protein complexes. Liron Bar-Peled is seeking scientists (masters, MD or PhD) with a strong mechanistic mindset who are excited to apply high-content, data-rich approaches to uncover fundamental biochemical and cell biological mechanisms.