TY  - JOUR
A1  - Jeanclos, Elisabeth
A1  - Schlötzer, Jan
A1  - Hadamek, Kerstin
A1  - Yuan-Chen, Natalia
A1  - Alwahsh, Mohammad
A1  - Hollmann, Robert
A1  - Fratz, Stefanie
A1  - Yesilyurt-Gerhards, Dilan
A1  - Frankenbach, Tina
A1  - Engelmann, Daria
A1  - Keller, Angelika
A1  - Kaestner, Alexandra
A1  - Schmitz, Werner
A1  - Neuenschwander, Martin
A1  - Hergenröder, Roland
A1  - Sotriffer, Christoph
A1  - von Kries, Jens Peter
A1  - Schindelin, Hermann
A1  - Gohla, Antje
T1  - Glycolytic flux control by drugging phosphoglycolate phosphatase
JF  - Nature Communications
N2  - 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.
KW  - phosphoglycolate phosphatase
KW  - glycolytic flux control
KW  - intrinsic metabolism
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300928
VL  - 13
IS  - 1
ER  - 
TY  - JOUR
A1  - Diebold, Mathias
A1  - Schönemann, Lars
A1  - Eilers, Martin
A1  - Sotriffer, Christoph
A1  - Schindelin, Hermann
T1  - Crystal structure of a covalently linked Aurora-A-MYCN complex
JF  - Acta Crystallographica
N2  - 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.
KW  - MYCNv
KW  - neuroblastoma cell
KW  - proteasome system
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318855
VL  - D79
SP  - 1
EP  - 9
ER  -