8RDX

PGGtase I in complex with probe BAY-6092

This is a non-PDB format compatible entry.

Summary for 8RDX

• Entry DOI: 10.2210/pdb8rdx/pdb
• Descriptor: Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha, Geranylgeranyl transferase type-1 subunit beta, ZINC ION, ... (7 entities in total)
• Functional Keywords: inhibitor, transferase
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 12
• Total formula weight: 466929.53

Authors

Steuber, H. (deposition date: 2023-12-08, release date: 2024-02-14, Last modification date: 2024-07-31)

Primary citation

Graham, K.,Lienau, P.,Bader, B.,Prechtl, S.,Naujoks, J.,Lesche, R.,Weiske, J.,Kuehnlenz, J.,Brzezinka, K.,Potze, L.,Zanconato, F.,Nicke, B.,Montebaur, A.,Bone, W.,Golfier, S.,Kaulfuss, S.,Kopitz, C.,Pilari, S.,Steuber, H.,Hayat, S.,Kamburov, A.,Steffen, A.,Schlicker, A.,Buchgraber, P.,Braeuer, N.,Font, N.A.,Heinrich, T.,Kuhnke, L.,Nowak-Reppel, K.,Stresemann, C.,Steigemann, P.,Walter, A.O.,Blotta, S.,Ocker, M.,Lakner, A.,von Nussbaum, F.,Mumberg, D.,Eis, K.,Piccolo, S.,Lange, M.
Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling.
Cell Chem Biol, 31:1247-, 2024

PubMed Abstract: 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.

PubMed: 38537632
DOI: 10.1016/j.chembiol.2024.02.013

Experimental method

X-RAY DIFFRACTION (3.67 Å)