Discovery of Inhibitors of the Kinases LATS1 and LATS2

Authors

• PJ Morris
• DD Duveau
• M Ceribelli
• FA Tosto
• L Evsen
• DN Love
• BS Scherer
• G Rai
• SB Hoyt
• CJ Thomas

Abstract

The Hippo pathway is a highly conserved biological pathway which regulates cell growth and proliferation. Within the Hippo pathway, the large tumor suppressor kinase 1 (LATS1) and large tumor suppressor kinase 2 (LATS2) play key roles as they phosphorylate the Yes-associated protein 1 (YAP1). Phosphorylation restricts YAP1 from translocating to the nucleus and promoting transcription. Inhibition of LATS1 and LATS2 thus prevents the phosphorylation of YAP1, allowing YAP1 to translocate to the nucleus, followed by the activation of cell growth and proliferation.
Recent studies have indicated that inhibition of LATS1 and LATS2 (LATS1/2) may have highly beneficial effects in the field of regenerative medicine. In order to examine this potential, we developed a selective inhibitor of LATS1/2 suitable for use in animal models. An initial hit was discovered via a kinome-wide screen of existing kinase inhibitors. Optimization of the hit improved its activity against LATS1/2, while removing its activity against its original kinase target. Further optimization of its ADME properties led to the lead compound NCGC00846691, which demonstrates in vivo inhibition of LATS1/2 in mouse models at 30 mg/kg dosing as well as acceleration of wound healing in both in vitro and in vivo skin models.

Scientific Focus Area: Molecular Pharmacology

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