Pharmacological targeting of large tumor suppressor kinases (LATS) 1 and 2 augments tissue repair and regeneration

Abstract

Background and Purpose

Large tumor suppressor kinases (LATS1 and 2) are core kinases of the Hippo signalling pathway, directly phosphorylate and inactivate the transcriptional coactivator Yes-associated protein 1 (YAP), playing a pivotal role in cell self-renewal and tissue regeneration. Hippo signalling inhibitors are urgently needed, both as tools for pharmacological studies of the Hippo pathway and as leads for developing novel, molecularly targeted drugs for the treatment of tissue injury and regeneration.

Experimental Approach

An enzyme linked immunosorbent assay (ELISA)-based in vitro high-throughput biochemical assay was used to the identification of a potent and reversible LATS1/2 inhibitor, N-(2-chloro-6-fluorobenzyl)-5-(1H-pyrrolo[2,3-b] pyridin-3-yl) furan-3-carboxamide (named as LPi-1). The regulation of LPi-1 on the activity of LATS1/2 kinases and YAP was evaluated both in vitro and in vivo. The murine models, including partial hepatectomy, paracetamol (acetaminophen/APAP)-induced liver hepatotoxicity and chemically induced colitis, were established to investigate the effect of LPi-1 on tissue repair and regeneration after injuries.

Key Results

LPi-1 effectively inhibited the activity of LATS1/2 kinases, thereby facilitating YAP activation to enhance the proliferation of hepatocytes in vitro. Moreover, LPi-1 was able to augment intestinal repair in mice following dextran sulphate sodium salt (DSS) treatment, as well as liver repair and regeneration in mice subjected to two-thirds partial hepatectomy or APAP-induced liver injury.

Conclusions and Implications

In conclusion, LPi-1 can serve as a valuable tool compound for exploring diverse biological functions associated with LATS1/2 kinases, as well as a promising lead compound for developing targeted therapeutic strategies aimed at enhancing tissue repair and regeneration.