Pharmacological targeting of the pseudokinase Her3.

Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines.

Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma.

Purpose: Targetable oncogenic alterations are detected more commonly in patients with non-small cell lung cancer (NSCLC) who never smoked cigarettes. For such patients, specific kinase inhibitors have emerged as effective clinical treatments. However, the currently known oncogenic alterations do not account for all never smokers who develop NSCLC.

The development of highly potent inhibitors for porcupine.

Porcupine is a member of the membrane-bound O-acyltransferase family of proteins. It catalyzes the palmitoylation of Wnt proteins, a process required for their secretion and activity. We recently disclosed a class of small molecules (IWPs) as the first reported Porcn inhibitors.

Diverse chemical scaffolds support direct inhibition of the membrane-bound O-acyltransferase porcupine.

Secreted Wnt proteins constitute one of the largest families of intercellular signaling molecules in vertebrates with essential roles in embryonic development and adult tissue homeostasis. The functional redundancy of Wnt genes and the many forms of cellular responses they elicit, including some utilizing the transcriptional co-activator β-catenin, has limited the ability of classical genetic strategies to uncover their roles in vivo. We had previously identified a chemical compound class termed Inhibitor of Wnt Production (or IWP) that targets Porcupine (Porcn), an acyltransferase catalyzing the addition of fatty acid adducts onto Wnt proteins.

Drugging the cancer stem cell compartment: lessons learned from the hedgehog and Wnt signal transduction pathways.

Cell-cell communication mediated by the secreted Hedgehog (Hh) and Wnt signaling molecules is essential to the coordination of cell fate decision making throughout the metazoan lifespan. From decades of genetically based interrogation, core components constituting the Hh and Wnt signal transduction pathways have been assembled, and a deep appreciation of how these signals elaborate distinct bodily tissues during development has been established. On the other hand, our incapacity to leverage similar genetic approaches to study adult organ systems has limited our understanding of how these molecules promote tissue renewal and regeneration through stem cell regulation.

Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.

The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/beta-catenin pathway activity. With these small molecules, we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue.