Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs.
Nathaniel R KastanSanyukta OakRui LiangLeigh BaxtRobert W MyersJohn GinnNigel LivertonDavid J HugginsJohn PichardoMatthew PaulThomas S CarrollAaron NagielKsenia GnedevaA J HudspethPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
The Hippo signaling pathway acts as a brake on regeneration in many tissues. This cascade of kinases culminates in the phosphorylation of the transcriptional cofactors Yap and Taz, whose concentration in the nucleus consequently remains low. Various types of cellular signals can reduce phosphorylation, however, resulting in the accumulation of Yap and Taz in the nucleus and subsequently in mitosis. We earlier identified a small molecule, TRULI, that blocks the final kinases in the pathway, Lats1 and Lats2, and thus elicits proliferation of several cell types that are ordinarily postmitotic and aids regeneration in mammals. In the present study, we present the results of chemical modification of the original compound and demonstrate that a derivative, TDI-011536, is an effective blocker of Lats kinases in vitro at nanomolar concentrations. The compound fosters extensive proliferation in retinal organoids derived from human induced pluripotent stem cells. Intraperitoneal administration of the substance to mice suppresses Yap phosphorylation for several hours and induces transcriptional activation of Yap target genes in the heart, liver, and skin. Moreover, the compound initiates the proliferation of cardiomyocytes in adult mice following cardiac cryolesions. After further chemical refinement, related compounds might prove useful in protective and regenerative therapies.
Keyphrases
- signaling pathway
- induced pluripotent stem cells
- stem cells
- small molecule
- pi k akt
- gene expression
- wound healing
- cell therapy
- induced apoptosis
- protein kinase
- epithelial mesenchymal transition
- high fat diet induced
- transcription factor
- mesenchymal stem cells
- endothelial cells
- single cell
- type diabetes
- diabetic retinopathy
- heart failure
- insulin resistance
- genome wide
- metabolic syndrome
- antiretroviral therapy
- adipose tissue
- heat shock
- young adults
- wild type
- cell proliferation
- heat shock protein
- heat stress