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

  • J Med Chem. 2025 Jul 10;68(13):13591-13608. doi: 10.1021/acs.jmedchem.5c00350.
Kenji Namoto  1 ,  Eric Vangrevelinghe  1 ,  Rainer Machauer  1 ,  Dirk Behnke  1 ,  Nicole Buschmann  1 ,  Julie Lachal  1 ,  Kathrin Schipp  1 ,  Mickael Sorge  1 ,  Kerstin Barker  1 ,  Francesca Fabbiani  1 ,  Philippe Piechon  1 ,  Lauren E Connor  1 ,  Stephane Laurent  1 ,  Felix Lohmann  1 ,  Vincent Unterreiner  1 ,  Elizabeth L George  2 ,  Emily Redmond  2 ,  Louis Wang  2 ,  Clemens Scheufler  1 ,  Bindi Sohal  1 ,  Andreas W Sailer  1 ,  Ralf Glatthar  1 ,  Jan S Tchorz  1 ,  Jürgen Maibaum  1
Affiliations
  • 1. Novartis Biomedical Research, CH-4002 Basel, Switzerland.
  • 2. Novartis Biomedical Research, Cambridge, Massachusetts 02139, United States.
PMID: 40574495 DOI: 10.1021/acs.jmedchem.5c00350
Abstract

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 1 for potency, binding efficiency, and physicochemical properties, leading to a highly selective, cellularly active, and orally available tool compound 7 (NIBR-LTSi) that demonstrated ex vivo target engagement and in vivo YAP target gene activation in rodents.