Using systematic physical and functional screens, Dr. Attisano’s lab has identified a kinase, NUAK2 (& the closely related NUAK1) that acts to inhibit the Hippo kinase cassette in cancer cell lines. They have shown that gene knockdown or small molecule inhibition of NUAKs restores pathway activity & inhibits tumorigenic properties in cells & in a mouse model. High expression of NUAK1 & 2 has also been confirmed in a subset of aggressive colorectal & bladder cancers. In collaboration with the OICR Drug Discovery Program, the group has undertaken efforts to identify novel potent small molecule inhibitors of NUAKs. Numerous experimental tools, including in-vitro and cell-based assays (in low & high-throughput formats) have been developed to measure Hippo pathway activity and confirm on-target effects. Through these efforts, the team has generated novel inhibitors of the NUAKs that demonstrate potent activity in both biochemical and cell based assays
The Hippo signaling pathway is a key regulator of tissue growth and organogenesis. At the molecular level, the Hippo kinase cassette controls the activity of the transcriptional regulators, YAP/TAZ. In most solid tumours, YAP/TAZ are uncoupled from this Hippo kinase cassette, and thus are constitutively nuclear and drive pro-oncogenic transcriptional programs. YAP/TAZ activity promotes proliferation, migration, invasion and maintenance of cancer stem cell traits. Although active YAP/TAZ is a hallmark of cancer, mutations in pathway components are rare, thus there is a pressing need to identify new targetable nodes. Compounds that restore pathway activity in vitro or in vivo have not been previously described. Our researchers have identified a kinase that negatively-regulates the Hippo pathway and have shown that knockdown or small molecule inhibition of this kinase restores pathway activity and inhibits tumorigenic properties in cells and in mice.
Proprietary compounds are being progressed through in vitro, cell-based and animal models.