Laboratory of Xu Wu, Ph.D
Call 617-726-4438
Email: xuwu@mgh.harvard.edu
6177264438
xuwu@mgh.harvard.edu
Overview
The Laboratory of Xu Wu, PhD, at Mass General is focused on studying protein lipidation in regulating cellular functions (self-renewal, differentiation, proliferation and chromatin remodeling) using chemical and genomic tools. We identify novel therapeutic targets in various inflammatory, degenerative diseases and cancers, and develop chemical tool and probes to target the unconventional “undruggable” targets.
Research Projects
Chemical Approaches for Posttranslational Protein Palmitoylation
Protein S-palmitoylation links a C16 palmitoyl group to the cysteine residues of proteins. This dynamic process spatially and temporally control protein functions, through modulating localization, trafficking, stability, complex formation and activities. Mechanistically, protein palmitoylation could be mediated by enzymatic and non-enzymatic processes. The non-enzymatic autopalmitoylation of proteins occurs with fatty acyl-CoA binding to proteins and directly acylating a reactive cysteine residue located near the lipid binding site, and has not been explored extensively. The crystal structures of several autopalmitoylated proteins, such as ZDHHC20, TEADs, Bet3, suggest that a common hydrophobic cavity exists in these proteins, which potentially accommodates the fatty acyl chain and stabilizes the protein-lipid complex. Therefore, it is reasonable to speculate that autopalmitoylated proteins may commonly possess a hydrophobic cavity, which in turn confers their druggability. Thus, mining autopalmitoylated proteome might uncover new druggable targets.
To this end, we are interested in using combinatorial synthesis, affinity-based proteomics and medicinal chemistry to address the key questions of autopalmitoylation: 1) what proteins are “autopalmitoylated”? 2) What are the functions and mechanisms of protein autopalmitoylation? 3) How cellular fatty acyl-CoA metabolism is regulating protein functions through “autopalmitoylation”?
Chemical Approaches to Dissect Signal cross-talking and “Rewiring” in Degenerative Diseases and Cancer
Cellular behaviors are regulated by a complex network of signal transduction pathways. The precise coordination and orchestration of multiple signaling pathways are essential for proper cellular functions. In diseases like cancer, oncogenic events often “rewire” the signaling network, resulting aberrant cell growth, survival and motility through non-canonical signaling cascades. Identification of small molecule tools that regulate the “nodes” of the crosstalk would be very important to understand the “rewired” signaling network and develop novel and effective therapeutics.
One essential question that we would like to understand is how cell growth is coordinated through multiple signals including growth factors, cell-cell contact and nutrients. We developed high throughput screening strategies to interrogate the signaling networks involving Wnt, Hippo, NFB and other signaling and their interactions in cancer and immunity. We are developing novel chemical modulators of these networks and pharmacologically validating novel therapeutic targets for cancer and degenerative diseases.
Targeting lipidation pockets of “undruggable” targets using chemical tool.
Recently, several non-enzymatic auto-S-fatty acylation of proteins have been characterized, revealing novel functions in regulating normal development and diseases. Our work in TEAD autopalmitoylation led to discovery of multiple small molecule inhibitors of TEADs, which are potential therapeutic agents for cancers with deregulated Hippo pathway. In addition, The crystal structures of auto-S-fatty acylated proteins all revealed a hydrophobic pocket to accommodate lipid binding. It is speculated that such hydrophobic pocket could be a common feature of many auto-S-fatty acylated proteins. Such unique structural feature provides a basis for rational drug design. More importantly, the inherent active cysteine near this hydrophobic pocket allows the development of irreversible inhibitors. Such approach opens a door to target previously “undruggable” targets to expand the “druggable” proteome. Moreover, these compounds provide novel chemical tools to decipher the functions of protein auto-S-fatty acylation in complex biological networks.