title: Halogen-enriched fragment libraries as leads for drug rescue of mutant p53.
abstract: The destabilizing p53 cancer mutation Y220C creates a druggable surface crevice. We developed a strategy exploiting halogen bonding for lead discovery to stabilize the mutant with small molecules. We designed halogen-enriched fragment libraries (HEFLibs) as starting points to complement classical approaches. From screening of HEFLibs and subsequent structure-guided design, we developed substituted 2-(aminomethyl)-4-ethynyl-6-iodophenols as p53-Y220C stabilizers. Crystal structures of their complexes highlight two key features: (i) a central scaffold with a robust binding mode anchored by halogen bonding of an iodine with a main-chain carbonyl and (ii) an acetylene linker, enabling the targeting of an additional subsite in the crevice. The best binders showed induction of apoptosis in a human cancer cell line with homozygous Y220C mutation. Our structural and biophysical data suggest a more widespread applicability of HEFLibs in drug discovery.
authors.affiliation: Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Wilcken
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Liu
authors.forename: Markus O
authors.initials: MO
authors.lastname: Zimmermann
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: Alan R
authors.initials: AR
authors.lastname: Fersht
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Joerger
authors.forename: Frank M
authors.initials: FM
authors.lastname: Boeckler
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D006219:Halogens / Q000494:pharmacology*; D006801:Humans; D050505:Mutant Proteins; D009154:Mutation; D055550:Protein Stability / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000235:genetics*
chemical_list: D006219:Halogens; D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53