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Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52.
J Med Chem. 2012 May 10; 55(9):4114-22.JM

Abstract

The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified α-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography.

Authors+Show Affiliations

Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 Munich, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22455444

Citation

Gopalakrishnan, Ranganath, et al. "Evaluation of Synthetic FK506 Analogues as Ligands for the FK506-binding Proteins 51 and 52." Journal of Medicinal Chemistry, vol. 55, no. 9, 2012, pp. 4114-22.
Gopalakrishnan R, Kozany C, Gaali S, et al. Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52. J Med Chem. 2012;55(9):4114-22.
Gopalakrishnan, R., Kozany, C., Gaali, S., Kress, C., Hoogeland, B., Bracher, A., & Hausch, F. (2012). Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52. Journal of Medicinal Chemistry, 55(9), 4114-22. https://doi.org/10.1021/jm201746x
Gopalakrishnan R, et al. Evaluation of Synthetic FK506 Analogues as Ligands for the FK506-binding Proteins 51 and 52. J Med Chem. 2012 May 10;55(9):4114-22. PubMed PMID: 22455444.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52. AU - Gopalakrishnan,Ranganath, AU - Kozany,Christian, AU - Gaali,Steffen, AU - Kress,Christoph, AU - Hoogeland,Bastiaan, AU - Bracher,Andreas, AU - Hausch,Felix, Y1 - 2012/04/19/ PY - 2012/3/30/entrez PY - 2012/3/30/pubmed PY - 2012/9/13/medline SP - 4114 EP - 22 JF - Journal of medicinal chemistry JO - J Med Chem VL - 55 IS - 9 N2 - The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified α-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/22455444/Evaluation_of_synthetic_FK506_analogues_as_ligands_for_the_FK506_binding_proteins_51_and_52_ L2 - https://doi.org/10.1021/jm201746x DB - PRIME DP - Unbound Medicine ER -