M. Madan Babu Lab

GPCRs belong to a unique family of proteins in that anything we learn from one can be extrapolated to other members, facilitating accelerated discovery. We are particularly interested in how GPCRs are regulated and how selectivity in signaling is achieved. GPCRs are excellent drug targets because of their physical location on the cell surface, but surprisingly few FDA-approved drugs targeting GPCRs have had a clinical impact in oncology. This is likely because slight alterations in the genome can cause significant variation in GPCR signaling, which causes preclinical failure of small molecules due to lack of efficacy or off-target effects. Can we create a map that allows us to infer the impact of mutations and find better therapeutics? Each step of GPCR regulation (from transcription to isoform splicing to post-translational modification and degradation) is a potential intervention point. We are working to understand the role of GPCRs in pediatric cancer and define new therapeutic vulnerabilities.

The canonical structure-function paradigm was transformational for drug discovery, but we now recognize that only 60% of protein sequence space is highly structured. The remainder is comprised of intrinsically disordered protein regions (IDRs). IDRs are found in several clinically relevant protein families, including kinases, zinc fingers, and GPCRs. Our laboratory is developing new experimental and computational methods to determine which parts of IDRs are critical for function and subcellular compartmentalization. New classes of cancer therapeutics are being designed (LYTACs, PROTACs, etc.), and a more thorough understanding of IDRs may contribute to the optimization and improvement of these approaches. 

Another focus of our Lab has direct relevance for pediatric cancer – the construction of cancer dependency maps for pediatric tumors. In collaboration with Dr Charles Roberts, and an interdisciplinary team of scientists at St. Jude and beyond, we are working to identify the molecular basis of cancer vulnerabilities. This work has potential to open up a new horizon of therapeutic opportunities by identifying and understanding which dispensable genes are uniquely critical in pediatric cancers. In this manner, we hope to identify druggable targets.