Chemical and Structural Approaches to Study Energy Homeostasis Pathways in Cancer and Metabolic disorders

Project Summary The overall research in the Lazarus Lab revolves around studying energy and protein homeostasis as it relates to human disease using chemical biology and structural biology. We have several multidisciplinary projects around this topic, including studying the ULK family of autophagy kinases and pseudokinases, lysine metabolism disorders, and other kinases related to diabetes and cancer. Over the last 4 years, we have used crystallography and chemical biology to help develop highly potent inhibitors of the metabolic sensor O-GlcNAc transferase, solved the first structures and identify the first chemical probes of the ULK pseudokinase linked to schizophrenia ULK4, and helped elucidate the first structure of an enzyme in the lysine metabolic pathway DHTKD1. Our goals over the next five-year period include further understanding of the ULK family of kinases. ULK1 and ULK2 are the main initiating enzymes for the autophagy pathway, a conserved metabolic pathway whereby cellular components get degraded for quality control and energy generation during starvation. The pathway is thought to be critical in diseases ranging from cancer to Alzheimer’s disease, yet there are still major gaps in our understanding of the pathway. What happens to cells when you inhibit autophagy at different stages of the pathway in different disease models using selective probes? What is the role of the mysterious family member ULK4, which has no catalytic activity but binds ATP with nanomolar potency and likely has a function for the ATP binding. Another major goal involves the lysine metabolic pathway, in which several inborn errors of metabolism are found. How do the enzymes in this pathway function, and can inhibiting other enzymes in this pathway block the toxic buildup of intermediates that arise in glutaric aciduria patients? The overall vision of the research program is to develop chemical probes and obtain high-resolution crystal structures to better understand key enzymes in these metabolic pathways and determine if they are therapeutic targets for human diseases. Within the context of the Mount Sinai research community, we are well-positioned to collaborate with our colleagues to leverage our strength in chemical and structural biology to provide molecular understanding that synergizes with our colleagues’ expertise in human biology or medicinal chemistry, like our overarching collaboration with the Drug Discovery Institute here and our collaborations that involve cancer, genetic diseases, diabetes, and neurodegeneration. As new opportunities arise, we can provide our expertise in the molecular underpinnings of glycosyltransferases, kinases and pseudokinases, and protein degradation pathways to develop new projects supported by the MIRA funding, while still focusing on the core projects described above.