Title | Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Kastan NR, Oak S, Liang R, Baxt L, Myers RW, Ginn J, Liverton N, Huggins DJ, Pichardo J, Paul M, Carroll TS, Nagiel A, Gnedeva K, Hudspeth AJ |
Journal | Proc Natl Acad Sci U S A |
Volume | 119 |
Issue | 28 |
Pagination | e2206113119 |
Date Published | 2022 Jul 12 |
ISSN | 1091-6490 |
Keywords | Animals, Cell Proliferation, Heart, Humans, Induced Pluripotent Stem Cells, Liver Regeneration, Mice, Organoids, Phosphorylation, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Regeneration, Retina, Skin Physiological Phenomena, Transcription, Genetic, Transcriptional Activation, YAP-Signaling Proteins |
Abstract | 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. |
DOI | 10.1073/pnas.2206113119 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 35867764 |
PubMed Central ID | PMC9282237 |
Grant List | 0 / / Howard Hughes Medical Institute (HHMI) / GM007739 / / HHS | NIH | National Institute of General Medical Sciences (NIGMS) / K08EY030924 / / HHS | NIH | National Eye Institute (NEI) / DC016984 / / HSS | NIH | National Institute for Deafness and other Communication Disorders / 0 / / The Rockefeller University / 0 / / Therapeutics Discovery Institute / |
Submitted by bel2021 on August 23, 2022 - 10:06am