@article{DieboldSchoenemannEilersetal.2023,
  author    = {Diebold, Mathias and Sch{\"o}nemann, Lars and Eilers, Martin and Sotriffer, Christoph and Schindelin, Hermann},
  title     = {Crystal structure of a covalently linked Aurora-A-MYCN complex},
  series = {Acta Crystallographica},
  volume    = {D79},
  journal   = {Acta Crystallographica},
  doi       = {10.1107/s2059798322011433},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318855},
  pages     = {1 -- 9},
  year      = {2023},
  abstract  = {Formation of the Aurora-A-MYCN complex increases levels of the oncogenic transcription factor MYCN in neuroblastoma cells by abrogating its degradation through the ubiquitin proteasome system. While some small-molecule inhibitors of Aurora-A were shown to destabilize MYCN, clinical trials have not been satisfactory to date. MYCN itself is considered to be `undruggable' due to its large intrinsically disordered regions. Targeting the Aurora-A-MYCN complex rather than Aurora-A or MYCN alone will open new possibilities for drug development and screening campaigns. To overcome the challenges that a ternary system composed of Aurora-A, MYCN and a small molecule entails, a covalently cross-linked construct of the Aurora-A-MYCN complex was designed, expressed and characterized, thus enabling screening and design campaigns to identify selective binders.},
  language  = {en}
}
@article{JeanclosSchloetzerHadameketal.2022,
  author    = {Jeanclos, Elisabeth and Schl{\"o}tzer, Jan and Hadamek, Kerstin and Yuan-Chen, Natalia and Alwahsh, Mohammad and Hollmann, Robert and Fratz, Stefanie and Yesilyurt-Gerhards, Dilan and Frankenbach, Tina and Engelmann, Daria and Keller, Angelika and Kaestner, Alexandra and Schmitz, Werner and Neuenschwander, Martin and Hergenr{\"o}der, Roland and Sotriffer, Christoph and von Kries, Jens Peter and Schindelin, Hermann and Gohla, Antje},
  title     = {Glycolytic flux control by drugging phosphoglycolate phosphatase},
  series = {Nature Communications},
  volume    = {13},
  journal   = {Nature Communications},
  number    = {1},
  doi       = {10.1038/s41467-022-34228-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300928},
  year      = {2022},
  abstract  = {Targeting the intrinsic metabolism of immune or tumor cells is a therapeutic strategy in autoimmunity, chronic inflammation or cancer. Metabolite repair enzymes may represent an alternative target class for selective metabolic inhibition, but pharmacological tools to test this concept are needed. Here, we demonstrate that phosphoglycolate phosphatase (PGP), a prototypical metabolite repair enzyme in glycolysis, is a pharmacologically actionable target. Using a combination of small molecule screening, protein crystallography, molecular dynamics simulations and NMR metabolomics, we discover and analyze a compound (CP1) that inhibits PGP with high selectivity and submicromolar potency. CP1 locks the phosphatase in a catalytically inactive conformation, dampens glycolytic flux, and phenocopies effects of cellular PGP-deficiency. This study provides key insights into effective and precise PGP targeting, at the same time validating an allosteric approach to control glycolysis that could advance discoveries of innovative therapeutic candidates.},
  language  = {en}
}
@article{BotheHaenzelmannBoehleretal.2022,
  author    = {Bothe, Sebastian and H{\"a}nzelmann, Petra and B{\"o}hler, Stephan and Kehrein, Josef and Zehe, Markus and Wiedemann, Christoph and Hellmich, Ute A. and Brenk, Ruth and Schindelin, Hermann and Sotriffer, Christoph},
  title     = {Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97},
  series = {Communications Chemistry},
  volume    = {5},
  journal   = {Communications Chemistry},
  number    = {1},
  doi       = {10.1038/s42004-022-00782-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300821},
  year      = {2022},
  abstract  = {Biosensor techniques have become increasingly important for fragment-based drug discovery during the last years. The AAA+ ATPase p97 is an essential protein with key roles in protein homeostasis and a possible target for cancer chemotherapy. Currently available p97 inhibitors address its ATPase activity and globally impair p97-mediated processes. In contrast, inhibition of cofactor binding to the N-domain by a protein-protein-interaction inhibitor would enable the selective targeting of specific p97 functions. Here, we describe a biolayer interferometry-based fragment screen targeting the N-domain of p97 and demonstrate that a region known as SHP-motif binding site can be targeted with small molecules. Guided by molecular dynamics simulations, the binding sites of selected screening hits were postulated and experimentally validated using protein- and ligand-based NMR techniques, as well as X-ray crystallography, ultimately resulting in the first structure of a small molecule in complex with the N-domain of p97. The identified fragments provide insights into how this region could be targeted and present first chemical starting points for the development of a protein-protein interaction inhibitor preventing the binding of selected cofactors to p97.},
  language  = {en}
}