Bioactive small molecule development- LATS program

National Center For Advancing Translational Sciences

Investigators

Abstract

Originally discovered in 1995 while searching for tumor-suppressor genes in the fruit-fly D. melanogaster the Hippo signaling pathway is a highly conserved signal transduction cascade that acts as central regulator of organ size control and tissue homeostasis during development. Hippo integrates a diverse set of extracellular signals, including cell-cell contact, cell polarity, mechanical cues and surface receptors engagement into a highly conserved protein kinase cascade that ultimately inhibits cell proliferation. In mammals, the mammalian sterile 20-like kinases MST1 and MST2 phosphorylate and activate the downstream kinases LATS1 and LATS2 which, in turn, phosphorylate the transcriptional coactivators YAP/TAZ inhibiting their function via cytoplasmic sequestration and/or phosphorylation-induced proteasomal degradation. LATS inhibition has been shown to promote proliferative regeneration of sensory hair cells in murine hears, to support proliferation of mice cardiomyocytes following cardiac cryo-lesions and to accelerate liver regeneration following partial hepatectomy in mice. This program aims to develop a highly potent an selective LATS1/2 inhibitor.