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Rapid, Structure-Based Exploration of Pipecolic Acid Amides as Novel Selective Antagonists of the FK506-Binding Protein 51.

Gaali S, Feng X, Hähle A, Sippel C, Bracher A, Hausch F
J Med Chem 59 2410-22 (2016)
Cited: 18 times
EuropePMC logo PMID: 26954324

Abstract

The FK506-binding protein 51 (FKBP51) is a key regulator of stress hormone receptors and an established risk factor for stress-related disorders. Drug development for FKBP51 has been impaired by the structurally similar but functionally opposing homologue FKBP52. High selectivity between FKBP51 and FKBP52 can be achieved by ligands that stabilize a recently discovered FKBP51-favoring conformation. However, drug-like parameters for these ligands remained unfavorable. In the present study, we replaced the potentially labile pipecolic ester group of previous FKBP51 ligands by various low molecular weight amides. This resulted in the first series of pipecolic acid amides, which had much lower molecular weights without affecting FKBP51 selectivity. We discovered a geminally substituted cyclopentyl amide as a preferred FKBP51-binding motif and elucidated its binding mode to provide a new lead structure for future drug optimization.

Articles - 5diu mentioned but not cited (1)

  1. Discovery of pentapeptide-inhibitor hits targeting FKBP51 by combining computational modeling and X-ray crystallography. Han JT, Zhu Y, Pan DB, Xue HX, Wang S, Peng Y, Liu H, He YX, Yao X. Comput Struct Biotechnol J 19 4079-4091 (2021)


Reviews citing this publication (7)

  1. FKBP Ligands-Where We Are and Where to Go? Kolos JM, Voll AM, Bauder M, Hausch F. Front Pharmacol 9 1425 (2018)
  2. Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds. Dunyak BM, Gestwicki JE. J Med Chem 59 9622-9644 (2016)
  3. The Many Faces of FKBP51. Hähle A, Merz S, Meyners C, Hausch F. Biomolecules 9 E35 (2019)
  4. Inhibitors and chemical probes for molecular chaperone networks. Gestwicki JE, Shao H. J Biol Chem 294 2151-2161 (2019)
  5. Diverse structures, functions and uses of FK506 binding proteins. Bonner JM, Boulianne GL. Cell Signal 38 97-105 (2017)
  6. Analysis of the Selective Antagonist SAFit2 as a Chemical Probe for the FK506-Binding Protein 51. Buffa V, Knaup FH, Heymann T, Springer M, Schmidt MV, Hausch F. ACS Pharmacol Transl Sci 6 361-371 (2023)
  7. Peptidylprolyl Isomerases as In Vivo Carriers for Drugs That Target Various Intracellular Entities. Galat A. Biomolecules 7 E72 (2017)

Articles citing this publication (10)

  1. FKBP51 Immunohistochemical Expression: A New Prognostic Biomarker for OSCC? Russo D, Merolla F, Mascolo M, Ilardi G, Romano S, Varricchio S, Napolitano V, Celetti A, Postiglione L, Di Lorenzo PP, Califano L, Dell'Aversana GO, Astarita F, Romano MF, Staibano S. Int J Mol Sci 18 E443 (2017)
  2. Molecular dynamics simulation, binding free energy calculation and unbinding pathway analysis on selectivity difference between FKBP51 and FKBP52: Insight into the molecular mechanism of isoform selectivity. Shi D, Bai Q, Zhou S, Liu X, Liu H, Yao X. Proteins 86 43-56 (2018)
  3. FKBP51 and FKBP52 regulate androgen receptor dimerization and proliferation in prostate cancer cells. Maeda K, Habara M, Kawaguchi M, Matsumoto H, Hanaki S, Masaki T, Sato Y, Matsuyama H, Kunieda K, Nakagawa H, Shimada M. Mol Oncol 16 940-956 (2022)
  4. Synthesis and Neurotrophic Activity Studies of Illicium Sesquiterpene Natural Product Analogues. Richers J, Pöthig A, Herdtweck E, Sippel C, Hausch F, Tiefenbacher K. Chemistry 23 3178-3183 (2017)
  5. Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity. Voll AM, Meyners C, Taubert MC, Bajaj T, Heymann T, Merz S, Charalampidou A, Kolos J, Purder PL, Geiger TM, Wessig P, Gassen NC, Bracher A, Hausch F. Angew Chem Int Ed Engl 60 13257-13263 (2021)
  6. Expression of FK506-binding protein 51 (FKBP51) in Mycosis fungoides. Mascolo M, Romano MF, Ilardi G, Romano S, Baldo A, Scalvenzi M, Argenziano G, Merolla F, Russo D, Varricchio S, Pagliuca F, Russo M, Ciancia G, De Rosa G, Staibano S. J Eur Acad Dermatol Venereol 32 735-744 (2018)
  7. Fenton-Chemistry-Based Oxidative Modification of Proteins Reflects Their Conformation. Nehls T, Heymann T, Meyners C, Hausch F, Lermyte F. Int J Mol Sci 22 9927 (2021)
  8. Binding pocket stabilization by high-throughput screening of yeast display libraries. Lerma Romero JA, Meyners C, Christmann A, Reinbold LM, Charalampidou A, Hausch F, Kolmar H. Front Mol Biosci 9 1023131 (2022)
  9. Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents. Xue W, Wang Y, Lian X, Li X, Pang J, Kirchmair J, Wu K, Han Z, You X, Zhang H, Xia J, Wu S. J Enzyme Inhib Med Chem 37 1620-1631 (2022)
  10. FKBP51 and FKBP12.6-Novel and tight interactors of Glomulin. Hähle A, Geiger TM, Merz S, Meyners C, Tianqi M, Kolos J, Hausch F. PLoS One 14 e0221926 (2019)


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