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

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

Cited: 99 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 - 4agm mentioned but not cited (3)

  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)
  2. Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines. Baud MGJ, Bauer MR, Verduci L, Dingler FA, Patel KJ, Horil Roy D, Joerger AC, Fersht AR. Eur J Med Chem 152 101-114 (2018)
  3. Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight. Regad L, Chéron JB, Triki D, Senac C, Flatters D, Camproux AC. PLoS One 12 e0182972 (2017)


Reviews citing this publication (22)

  1. The Halogen Bond. Cavallo G, Metrangolo P, Milani R, Pilati T, Priimagi A, Resnati G, Terraneo G. Chem Rev 116 2478-2601 (2016)
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  5. Structural and Drug Targeting Insights on Mutant p53. Gomes AS, Ramos H, Inga A, Sousa E, Saraiva L. Cancers (Basel) 13 3344 (2021)
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  9. Roles of computational modelling in understanding p53 structure, biology, and its therapeutic targeting. Tan YS, Mhoumadi Y, Verma CS. J Mol Cell Biol 11 306-316 (2019)
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  11. Follow the Mutations: Toward Class-Specific, Small-Molecule Reactivation of p53. Loh SN. Biomolecules 10 E303 (2020)
  12. Making Connections: p53 and the Cathepsin Proteases as Co-Regulators of Cancer and Apoptosis. Soond SM, Savvateeva LV, Makarov VA, Gorokhovets NV, Townsend PA, Zamyatnin AA. Cancers (Basel) 12 E3476 (2020)
  13. Liquid chromatography enantioseparations of halogenated compounds on polysaccharide-based chiral stationary phases: role of halogen substituents in molecular recognition. Peluso P, Mamane V, Cossu S. Chirality 27 667-684 (2015)
  14. Therapeutic Strategies to Activate p53. Aguilar A, Wang S. Pharmaceuticals (Basel) 16 24 (2022)
  15. p53 and Zinc: A Malleable Relationship. Ha JH, Prela O, Carpizo DR, Loh SN. Front Mol Biosci 9 895887 (2022)
  16. Anticancer Therapeutic Strategies Targeting p53 Aggregation. Ferretti GDS, Quarti J, Dos Santos G, Rangel LP, Silva JL. Int J Mol Sci 23 11023 (2022)
  17. Disease-modifying therapy for proteinopathies: Can the exception become the rule? Bitan G. Prog Mol Biol Transl Sci 168 277-287 (2019)
  18. A role for bioinorganic chemistry in the reactivation of mutant p53 in cancer. Miller JJ, Kwan K, Gaiddon C, Storr T. J Biol Inorg Chem 27 393-403 (2022)
  19. Small-molecule correctors and stabilizers to target p53. Fallatah MMJ, Law FV, Chow WA, Kaiser P. Trends Pharmacol Sci 44 274-289 (2023)
  20. A new wave of innovations within the DNA damage response. Li Q, Qian W, Zhang Y, Hu L, Chen S, Xia Y. Signal Transduct Target Ther 8 338 (2023)
  21. Conformational stable alleno-acetylenic cyclophanes bearing chiral axes. Lahoz IR, Castro-Fernández S, Navarro-Vázquez A, Alonso-Gómez JL, Magdalena Cid M. Chirality 26 563-573 (2014)
  22. Principles and Applications of CF2X Moieties as Unconventional Halogen Bond Donors in Medicinal Chemistry, Chemical Biology, and Drug Discovery. Vaas S, Zimmermann MO, Schollmeyer D, Stahlecker J, Engelhardt MU, Rheinganz J, Drotleff B, Olfert M, Lämmerhofer M, Kramer M, Stehle T, Boeckler FM. J Med Chem 66 10202-10225 (2023)

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