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NUAK Inhibitors as Therapeutics for Cancer and Fibrosis
University Of Toronto
Small molecule
Oncology
Hit To Lead or Lead Optimization
Background
The Hippo signaling pathway is a key regulator of cell proliferation and cell death. High cell density and stress activate the pathway to stop cell proliferation and induce apoptosis. It has consequently been linked to diseases such as cancer and fibrosis. At the molecular level, the Hippo kinase cassette controls the activity of the transcriptional regulators, YAP and TAZ, through phosphorylation events. Phosphorylation of YAP and TAZ by a kinase of the Hippo pathway, LATS, results in cytoplasmic localization where these molecules cannot exert their function. However, unphosphorylated YAP and TAZ localize to the nucleus where they can interact with transcription factors (e.g. TEAD) to turn on gene transcription and promote pro-oncogenic, pro-fibrotic outcomes. This implies that molecules that promote TAP and TAZ phosphorylation can act as therapeutics for cancer and fibrosis.
Technology Overview
Researchers at the University of Toronto have identified a kinase, NUAK2 (& the closely related NUAK1), that promotes YAP and TAZ oncogenic and fibrotic activity. NUAK2 acts in a positive feed forward loop where it prevents the phosphorylation of YAP and TAZ by a Hippo kinase (Figure 1b). They have shown that gene knockdown or small molecule inhibition of NUAKs restores pathway activity and inhibits both tumorigenic and fibrotic properties in cells and in mice models. 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 confirming on-target effects. Through these efforts, the team has generated novel inhibitors (currently in the lead optimization stage) of the NUAKs that demonstrate potent activity in both cell-based assays and animal studies.
Mandeep K. Gill , Tania Christova
PCT-CA2022-050016 (2022.01.07)
Patent Family: AU, CA, CN, EU, JP, US
PCT-CA2022-050014 (2022.01.07)
Patent Family: AU, CA, CN, EU, JP, US
"A feed forward loop enforces YAP/TAZ signaling during tumorigenesis". Gill, M. et al. Nature Communications 2018, 9(1)
