2. Academic Validation
  3. Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs

Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs

  • Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2206113119. doi: 10.1073/pnas.2206113119.
Nathaniel R Kastan 1,  Sanyukta Oak 1,  Rui Liang 2,  Leigh Baxt 2,  Robert W Myers 2,  John Ginn 2,  Nigel Liverton 2,  David J Huggins 2 3,  John Pichardo 2,  Matthew Paul 4,  Thomas S Carroll 4,  Aaron Nagiel 5 6 7,  Ksenia Gnedeva 8 9,  A J Hudspeth 1
Affiliations

Affiliations

  • 1 Howard Hughes Medical Institute and Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY 10065.
  • 2 Tri-Institutional Therapeutics Discovery Institute, New York, NY 10021.
  • 3 Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065.
  • 4 Bioinformatics Resource Center, The Rockefeller University, New York, NY 10065.
  • 5 The Vision Center, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA 90027.
  • 6 The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027.
  • 7 Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
  • 8 Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90033.
  • 9 Tina and Rick Caruso Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angeles, CA 90033.
PMID: 35867764 DOI: 10.1073/pnas.2206113119
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.

Keywords

TRULI; cardiomyocyte; mouse; regeneration; retinal organoid.

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