Namoto Kenji, Vangrevelinghe Eric, Machauer Rainer, Behnke Dirk, Buschmann Nicole, Lachal Julie, Schipp Kathrin, Sorge Mickael, Barker Kerstin, Fabbiani Francesca, Piechon Philippe, Connor Lauren E, Laurent Stephane, Lohmann Felix, Unterreiner Vincent, George Elizabeth L, Redmond Emily, Wang Louis, Scheufler Clemens, Sohal Bindi, Sailer Andreas W, Glatthar Ralf, Tchorz Jan S, Maibaum Jürgen
Novartis Biomedical Research, CH-4002 Basel, Switzerland.
Novartis Biomedical Research, Cambridge, Massachusetts 02139, United States.
J Med Chem. 2025 Jul 10;68(13):13591-13608. doi: 10.1021/acs.jmedchem.5c00350. Epub 2025 Jun 26.
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 for potency, binding efficiency, and physicochemical properties, leading to a highly selective, cellularly active, and orally available tool compound (NIBR-LTSi) that demonstrated target engagement and in vivo YAP target gene activation in rodents.
大肿瘤抑制激酶LATS1和LATS2（LATS1/2）是丝氨酸/苏氨酸激酶，也是Hippo-YAP信号通路的核心调节因子。抑制LATS1/2可促进非磷酸化YAP的核转位，从而启动促进细胞增殖的下游级联反应。我们着手研究抑制LATS作为增强组织再生的治疗方法的潜力，并在此报告了一种基于结构的筛选命中化合物的优化，以提高其效力、结合效率和理化性质，从而得到一种具有高选择性、细胞活性且口服可用的工具化合物（NIBR-LTSi），该化合物在啮齿动物中显示出靶点结合和体内YAP靶基因激活作用。
