Namoto, Kenji, Vangrevelinghe, Eric, Machauer, Rainer, Behnke, Dirk, Buschmann, Nicole, Lachal, Julie, Schipp, Kathrin, Barker, Kerstin, Fabbiani, Francesca, Piechon, Philippe, Connor, Lauren, Laurent, Stephane, Lohmann, Felix, Unterreiner, Vincent, George, Elizabeth, Redmond, Emily, Wang, Louis, Scheufler, Clemens, Sohal, Bindi, Sailer, Andreas W., Glatthar, Ralf, Tchorz, Jan and Maibaum, Jürgen (2025) 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. Journal of medicinal chemistry. ISSN 1520-4804

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.

Item Type:	Article
Date Deposited:	15 Jul 2025 00:45
Last Modified:	15 Jul 2025 00:45
URI:	https://oak.novartis.com/id/eprint/55861