Discovery and optimization of a LATS1/2 kinase inhibitor for applications in wound healing and regenerative medicine

Authors

• P Hallaert
• L Miao
• M Martin
• L Collado
• S Barkdull
• A Coxon
• B Gryder
• I Brownell

Abstract

The evolutionarily conserved Hippo pathway plays a key role in organ size regulation and homeostasis by acting as a “brake” 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

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