Targeting the therapy resistance factors BAG3 und Bcl-xL in solid tumors

• Applicants: Professor Dr. Andreas Brunschweiger; Professor Dr. Oliver Koch; Professor Dr. Donat Kögel
• Subject Area: Pharmacy ; Biological and Biomimetic Chemistry ; Hematology, Oncology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398347929

• Final Report Year: 2024

Final Report Abstract

In the DFG-funded project, a DEL based on the hexT coding system was synthesized for the first time. Selection-based screening could be established and computational methods for DEL design and evaluation of DEL screens could be developed and successfully applied. DEL screens led to the identification of TEAD-Yap inhibitors with cellular activity. This led to two very high impact publications, novel insights into the oncogenic functions of BAG3 in therapy-resistant cancer, and several review papers. It has enabled the crucial step from pure synthesis and coding technology development to library development and screening of these libraries. Pending is the synthesis of molecules whose DNA barcodes were found in the later screens on BAG3 and Bcl-xL. These will be synthesized and made available for biological validation in future projects.

Publications

• BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells. Neoplasia, 20(3), 263-279.
  Das, Chandan Kanta; Linder, Benedikt; Bonn, Florian; Rothweiler, Florian; Dikic, Ivan; Michaelis, Martin; Cinatl, Jindrich; Mandal, Mahitosh & Kögel, Donat
  
• At the Crossroads of Apoptosis and Autophagy: Multiple Roles of the Co-Chaperone BAG3 in Stress and Therapy Resistance of Cancer. Cells, 9(3), 574.
  Kögel, Donat; Linder, Benedikt; Brunschweiger, Andreas; Chines, Silvia & Behl, Christian
  
• Reaction development for DNA-encoded library technology: From evolution to revolution?. Tetrahedron Letters, 61(22), 151889.
  Götte, Katharina; Chines, Silvia & Brunschweiger, Andreas
  
• Scanning Protein Surfaces with DNA‐Encoded Libraries. ChemMedChem, 16(7), 1048-1062.
  Kunig, Verena B. K.; Potowski, Marco; Klika, Škopić Mateja & Brunschweiger, Andreas
  
• TEAD–YAP Interaction Inhibitors and MDM2 Binders from DNA‐Encoded Indole‐Focused Ugi Peptidomimetics. Angewandte Chemie International Edition, 59(46), 20338-20342.
  Kunig, Verena B. K.; Potowski, Marco; Akbarzadeh, Mohammad; Klika, Škopić Mateja; dos Santos Smith, Denise; Arendt, Lukas; Dormuth, Ina; Adihou, Hélène; Andlovic, Blaž; Karatas, Hacer; Shaabani, Shabnam; Zarganes‐Tzitzikas, Tryfon; Neochoritis, Constantinos G.; Zhang, Ran; Groves, Matthew; Guéret, Stéphanie M.; Ottmann, Christian; Rahnenführer, Jörg; Fried, Roland ... & Brunschweiger, Andreas
  
• BAG3 is a negative regulator of ciliogenesis in glioblastoma and triple‐negative breast cancer cells. Journal of Cellular Biochemistry, 123(1), 77-90.
  Linder, Benedikt; Klein, Caterina; Hoffmann, Marina E.; Bonn, Florian; Dikic, Ivan & Kögel, Donat
  
• Navigating chemical reaction space – application to DNA-encoded chemistry. Chemical Science, 13(37), 11221-11231.
  Chines, Silvia; Ehrt, Christiane; Potowski, Marco; Biesenkamp, Felix; Grützbach, Lars; Brunner, Susanne; van den Broek, Frederik; Bali, Shilpa; Ickstadt, Katja & Brunschweiger, Andreas