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Halogen-enriched fragment libraries as leads for drug rescue of mutant p53.

Wilcken R, Liu X, Zimmermann MO, Rutherford TJ, Fersht AR, Joerger AC, Boeckler FM
J Am Chem Soc 134 6810-8 (2012)
Related entries: 2j1w, 2j1x, 2j1y, 2j1z, 2j20, 2j21, 4agl, 4agm, 4agn, 4ago, 4agq

Cited: 100 times
EuropePMC logo PMID: 22439615

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.

Articles - 4agp mentioned but not cited (5)

  1. Halogen-enriched fragment libraries as leads for drug rescue of mutant p53. Wilcken R, Liu X, Zimmermann MO, Rutherford TJ, Fersht AR, Joerger AC, Boeckler FM. J Am Chem Soc 134 6810-6818 (2012)
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Reviews citing this publication (22)

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  1. Structural basis for understanding oncogenic p53 mutations and designing rescue drugs.. Joerger AC, Ang HC, Fersht AR Proc Natl Acad Sci U S A 103 15056-61 (2006)

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