NIH Research Festival
The evolutionarily conserved Hippo pathway plays a key role in organ size regulation and homeostasis by acting as a ‚Äúbrake‚Äù on the activity of transcriptional coactivators YAP and TAZ. Central to the activity of this pathway is a kinase cascade involving LATS1/2, which inactivates the YAP/TAZ complex through serine phosphorylation and maintains its subcellular localization in the cytoplasm. In healthy cells, inhibition of LATS1/2 allows the YAP/TAZ complex to remain active and translocate to the nucleus, resulting in cell proliferation via mitosis. Recent studies indicate that LATS1/2 inhibition may have highly beneficial effects in the fields of regenerative medicine and wound healing, but the small number of potent, selective pharmacological options for LATS1/2 inhibition limits exploration of this hypothesis. In order to examine this potential, we endeavored to develop a selective kinase inhibitor for LATS1/2 suitable for use in animal models. A kinome-wide screen of existing commercial kinase inhibitors led us to our initial hit compound; further optimization of the hit simultaneously enhanced its activity against LATS1/2 and reduced activity against its original kinase target. Further optimization of its ADME properties resulted in our lead compound, which demonstrates excellent inhibition of LATS1/2 in murine models and may prove suitable for testing our regenerative medicine hypothesis.
Scientific Focus Area: Molecular Pharmacology
This page was last updated on Monday, September 25, 2023