Discovery and Optimization of Selective Inhibitors of Large Tumor Suppressor Kinases LATS1 and 2 for In Vivo Investigation of the Hippo-YAP Pathway in Tissue Regeneration
Large Tumor Suppressor kinases LATS1 and 2 (LATS1/2) are serine/threonine kinases and core regulators of the Hippo-YAP pathway. Inhibition of LATS1/2 promotes nuclear translocation of nonphosphorylated YAP, thereby initiating a downstream cascade promoting cell proliferation. We set out to investigate the potential of LATS inhibition as a therapeutic approach to enhance tissue regeneration and hereby report a structure-guided optimization of screening hit <b>1</b> for potency, binding efficiency, and physicochemical properties, leading to a highly selective, cellularly active, and orally available tool compound <b>7</b> (NIBR-LTSi) that demonstrated <i>ex vivo</i> target engagement and in vivo YAP target gene activation in rodents.
Authors
- Elizabeth George (ORCID: https://orcid.org/0000-0002-1274-7836)
- Rainer Machauer (ORCID: https://orcid.org/0000-0001-5081-6268)
- Clemens Scheufler (ORCID: https://orcid.org/0000-0002-3693-3529)
- Felix Lohmann (ORCID: https://orcid.org/0000-0001-6448-5885)
- Louis Wang
- Bindi Sohal
- Ralf Glatthar
- Mickaël Sorge
- F.P.A. Fabbiani
- Jan S. Tchorz (ORCID: https://orcid.org/0000-0003-1745-6621)
- Kerstin Barker
- Lauren E. Connor (ORCID: https://orcid.org/0000-0002-4626-8921)
- Eric Vangrevelinghe (ORCID: https://orcid.org/0000-0001-9788-0574)
- Andreas W. Sailer (ORCID: https://orcid.org/0000-0002-9015-7946)
- Vincent Unterreiner
- Julie Lachal
- Kenji Namoto (ORCID: https://orcid.org/0000-0003-2036-1674)
- Kathrin Schipp
- Stéphane Laurent
- Nicole Buschmann
- Philippe Piéchon
- Jürgen Maibaum
- Emily Redmond
- Dirk Behnke
Institutions
- Novartis (China) (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00350
- Citations
- 1
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 1.15