@article{KyriaziVothBaderetal.2024,
  author    = {Kyriazi, Despoina and Voth, Lea and Bader, Almke and Ewert, Wiebke and Gerlach, Juliane and Elfrink, Kerstin and Franz, Peter and Tsap, Mariana I. and Schirmer, Bastian and Damiano-Guercio, Julia and Hartmann, Falk K. and Plenge, Masina and Salari, Azam and Sch{\"o}ttelndreier, Dennis and Strienke, Katharina and Bresch, Nadine and Salinas, Claudio and Gutzeit, Herwig O. and Schaumann, Nora and Hussein, Kais and B{\"a}hre, Heike and Br{\"u}sch, Inga and Claus, Peter and Neumann, Detlef and Taft, Manuel H. and Shcherbata, Halyna R. and Ngezahayo, Anaclet and B{\"a}hler, Martin and Amiri, Mahdi and Kn{\"o}lker, Hans-Joachim and Preller, Matthias and Tsiavaliaris, Georgios},
  title     = {An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells},
  journal   = {Nature Communications},
  volume    = {15},
  issn      = {2041-1723},
  doi       = {10.1038/s41467-024-54181-6},
  institution = {Fachbereich Angewandte Naturwissenschaften},
  pages     = {9947},
  year      = {2024},
  abstract  = {Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin that originate from local disturbances in RhoA/ROCK-regulated signalling, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis. Combined with the non-toxic, non-pathological signatures of adhibin validated in organoids, mouse and Drosophila models, this mechanism of action provides the basis for developing anti-metastatic cancer therapies.},
  language  = {en}
}