%0 Journal Article
%T Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling.
%A Graham K
%A Lienau P
%A Bader B
%A Prechtl S
%A Naujoks J
%A Lesche R
%A Weiske J
%A Kuehnlenz J
%A Brzezinka K
%A Potze L
%A Zanconato F
%A Nicke B
%A Montebaur A
%A Bone W
%A Golfier S
%A Kaulfuss S
%A Kopitz C
%A Pilari S
%A Steuber H
%A Hayat S
%A Kamburov A
%A Steffen A
%A Schlicker A
%A Buchgraber P
%A Braeuer N
%A Font NA
%A Heinrich T
%A Kuhnke L
%A Nowak-Reppel K
%A Stresemann C
%A Steigemann P
%A Walter AO
%A Blotta S
%A Ocker M
%A Lakner A
%A von Nussbaum F
%A Mumberg D
%A Eis K
%A Piccolo S
%A Lange M
%J Cell Chem Biol
%V 31
%N 7
%D 2024 Jul 18
%M 38537632
%F 9.039
%R 10.1016/j.chembiol.2024.02.013
%X This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo.