title: Biosynthesis-driven structure-activity relationship study of premonensin-derivatives.
abstract: The controlled derivatization of natural products is of great importance for their use in drug discovery. The ideally rapid generation of compound libraries for structure-activity relationship studies is of particular concern. We here use modified biosynthesis for the generation of such a library of reduced polyketides to interfere with the oncogenic KRas pathway. The polyketide is derivatized via side chain alteration, and variations in its redox pattern and in its backbone chain length through manipulation in the corresponding polyketide synthase. Structural and biophysical analyses revealed the nature of the interaction between the polyketides and KRas-interacting protein PDE6δ. Non-natural polyketides with low nanomolar affinity to PDE6δ were identified.
authors.affiliation: Fakultät für Chemie und Biochemie, Organische Chemie 1, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany. frank.schulz@rub.de.
authors.forename: A
authors.initials: A
authors.lastname: Ismail-Ali
authors.affiliation: Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Str. 11, 44227 Dortmund, Germany. alfred.wittinghofer@mpi-dortmund.mpg.de.
authors.forename: E K
authors.initials: EK
authors.lastname: Fansa
authors.affiliation: Fakultät für Chemie und Biochemie, Organische Chemie 1, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany. frank.schulz@rub.de.
authors.forename: N
authors.initials: N
authors.lastname: Pryk
authors.affiliation: Centre d'Etudes et de Recherche sur le Médicament de Normandie UPRES EA 4258, Université de Caen Basse-Normandie, FR CNRS 3038 INC3 M, Bd Becquerel, 14032 Caen Cedex, France.
authors.forename: S
authors.initials: S
authors.lastname: Yahiaoui
authors.affiliation: Fakultät für Chemie und Biochemie, Organische Chemie 1, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany. frank.schulz@rub.de.
authors.forename: S
authors.initials: S
authors.lastname: Kushnir
authors.affiliation: Fakultät für Chemie und Biochemie, Organische Chemie 1, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany. frank.schulz@rub.de.
authors.forename: M
authors.initials: M
authors.lastname: Pflieger
authors.affiliation: Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Str. 11, 44227 Dortmund, Germany. alfred.wittinghofer@mpi-dortmund.mpg.de.
authors.forename: A
authors.initials: A
authors.lastname: Wittinghofer
authors.affiliation: Fakultät für Chemie und Biochemie, Organische Chemie 1, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany. frank.schulz@rub.de.
authors.forename: F
authors.initials: F
authors.lastname: Schulz
mesh_terms: D006801:Humans; D048630:Polyketide Synthases / Q000737:chemistry / Q000378:metabolism*; D061065:Polyketides / Q000737:chemistry / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C117307:KRAS protein, human; D061065:Polyketides; D048630:Polyketide Synthases; D016283:Proto-Oncogene Proteins p21(ras)