Small Molecule Activation of Yap for Inner-Ear Regeneration and Beyond

Author

Nathaniel Kastan

Date of Award

2020

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Hudspeth Laboratory

Abstract

Hippo signaling is an evolutionarily conserved pathway that restricts organ growth during development and suppresses regeneration in mature organs. Using a highthroughput phenotypic screen, we have identified a potent, non-toxic, and reversible inhibitor of Hippo signaling. An ATP-competitive inhibitor of Lats kinases, the compound causes Yap-dependent proliferation of murine supporting cells in the inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. The compound promotes the initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear. In conjunction with the Tri- Institutional Therapeutics Discovery Institute, we have thoroughly characterized the compound and generated a suite of over 60 derivatives with improved characteristics such as potency, pharmacokinetics, and specificity. Together, these compounds offer powerful tools for molecular investigations of development, stem cell biology, and regeneration; it is even plausible that drugs related to this novel thiazolimine class will prove useful in therapeutic contexts.

Comments

A Thesis Presented to the Faculty of the Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Kastan, Nathaniel, "Small Molecule Activation of Yap for Inner-Ear Regeneration and Beyond" (2020). Student Theses and Dissertations. 589.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/589