A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction

Ewa Surmiak; Aleksandra Twarda-Clapa; Krzysztof M. Zak; Bogdan Musielak; Marcin D. Tomala; Katarzyna Kubica; Przemyslaw Grudnik; Mariusz Madej; Mateusz Jablonski; Jan Potempa; Justyna Kalinowska-Tluscik; Alexander Dömling; Grzegorz Dubin; Tad A. Holak

doi:10.1021/acschembio.6b00596

A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction

Ewa Surmiak, Aleksandra Twarda-Clapa, Krzysztof M. Zak, Bogdan Musielak, Marcin D. Tomala, Katarzyna Kubica, Przemyslaw Grudnik, Mariusz Madej, Mateusz Jablonski, Jan Potempa, Justyna Kalinowska-Tluscik, Alexander Dömling, Grzegorz Dubin, Tad A. Holak

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Abstract

The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.

Original language	English
Pages (from-to)	3310-3318
Number of pages	9
Journal	ACS chemical biology
Volume	11
Issue number	12
DOIs	https://doi.org/10.1021/acschembio.6b00596
Publication status	Published - Dec-2016

Keywords

PROTEIN-PROTEIN INTERACTIONS
SMALL-MOLECULE INHIBITORS
STRUCTURE-BASED DESIGN
TUMOR-SUPPRESSOR P53
MDM2-P53 INTERACTION
NMR-SPECTROSCOPY
LIGAND-BINDING
DRUG DISCOVERY
CANCER-THERAPY
POTENT

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10.1021/acschembio.6b00596

A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one-Final publisher's version, 4.65 MBLicence: Taverne

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CCDC 1054957: Experimental Crystal Structure Determination
Surmiak, E. (Contributor), Twarda-Clapa, A. (Contributor), Zak, K. M. (Contributor), Musielak, B. (Contributor), Tomala, M. D. (Contributor), Kubica, K. (Contributor), Grudnik, P. (Contributor), Madej, M. (Contributor), Jablonski, M. (Contributor), Potempa, J. (Contributor), Kalinowska-Tluscik, J. (Contributor), Dömling, A. (Contributor), Dubin, G. (Contributor) & Holak, T. A. (Contributor), University of Groningen, 19-Mar-2015
DOI: 10.5517/ccdc.csd.cc14drw5
Dataset
CCDC 1054956: Experimental Crystal Structure Determination
Surmiak, E. (Contributor), Twarda-Clapa, A. (Contributor), Zak, K. M. (Contributor), Musielak, B. (Contributor), Tomala, M. D. (Contributor), Kubica, K. (Contributor), Grudnik, P. (Contributor), Madej, M. (Contributor), Jablonski, M. (Contributor), Potempa, J. (Contributor), Kalinowska-Tluscik, J. (Contributor), Dömling, A. (Contributor), Dubin, G. (Contributor) & Holak, T. A. (Contributor), University of Groningen, 19-Mar-2015
DOI: 10.5517/ccdc.csd.cc14drv4
Dataset
CCDC 1054955: Experimental Crystal Structure Determination
Surmiak, E. (Contributor), Twarda-Clapa, A. (Contributor), Zak, K. M. (Contributor), Musielak, B. (Contributor), Tomala, M. D. (Contributor), Kubica, K. (Contributor), Grudnik, P. (Contributor), Madej, M. (Contributor), Jablonski, M. (Contributor), Potempa, J. (Contributor), Kalinowska-Tluscik, J. (Contributor), Dömling, A. (Contributor), Dubin, G. (Contributor) & Holak, T. A. (Contributor), University of Groningen, 19-Mar-2015
DOI: 10.5517/ccdc.csd.cc14drt3
Dataset

Cite this

Surmiak, E., Twarda-Clapa, A., Zak, K. M., Musielak, B., Tomala, M. D., Kubica, K., Grudnik, P., Madej, M., Jablonski, M., Potempa, J., Kalinowska-Tluscik, J., Dömling, A., Dubin, G., & Holak, T. A. (2016). A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction. ACS chemical biology, 11(12), 3310-3318. https://doi.org/10.1021/acschembio.6b00596

@article{ae3654f26a914ae6a09c5d30b9f570cf,

title = "A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction",

abstract = "The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.",

keywords = "PROTEIN-PROTEIN INTERACTIONS, SMALL-MOLECULE INHIBITORS, STRUCTURE-BASED DESIGN, TUMOR-SUPPRESSOR P53, MDM2-P53 INTERACTION, NMR-SPECTROSCOPY, LIGAND-BINDING, DRUG DISCOVERY, CANCER-THERAPY, POTENT",

author = "Ewa Surmiak and Aleksandra Twarda-Clapa and Zak, {Krzysztof M.} and Bogdan Musielak and Tomala, {Marcin D.} and Katarzyna Kubica and Przemyslaw Grudnik and Mariusz Madej and Mateusz Jablonski and Jan Potempa and Justyna Kalinowska-Tluscik and Alexander D{\"o}mling and Grzegorz Dubin and Holak, {Tad A.}",

year = "2016",

month = dec,

doi = "10.1021/acschembio.6b00596",

language = "English",

volume = "11",

pages = "3310--3318",

journal = "ACS chemical biology",

issn = "1554-8929",

publisher = "AMER CHEMICAL SOC",

number = "12",

}

Surmiak, E, Twarda-Clapa, A, Zak, KM, Musielak, B, Tomala, MD, Kubica, K, Grudnik, P, Madej, M, Jablonski, M, Potempa, J, Kalinowska-Tluscik, J, Dömling, A, Dubin, G & Holak, TA 2016, 'A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction', ACS chemical biology, vol. 11, no. 12, pp. 3310-3318. https://doi.org/10.1021/acschembio.6b00596

TY - JOUR

T1 - A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction

AU - Surmiak, Ewa

AU - Twarda-Clapa, Aleksandra

AU - Zak, Krzysztof M.

AU - Musielak, Bogdan

AU - Tomala, Marcin D.

AU - Kubica, Katarzyna

AU - Grudnik, Przemyslaw

AU - Madej, Mariusz

AU - Jablonski, Mateusz

AU - Potempa, Jan

AU - Kalinowska-Tluscik, Justyna

AU - Dömling, Alexander

AU - Dubin, Grzegorz

AU - Holak, Tad A.

PY - 2016/12

Y1 - 2016/12

N2 - The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.

AB - The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.

KW - PROTEIN-PROTEIN INTERACTIONS

KW - SMALL-MOLECULE INHIBITORS

KW - STRUCTURE-BASED DESIGN

KW - TUMOR-SUPPRESSOR P53

KW - MDM2-P53 INTERACTION

KW - NMR-SPECTROSCOPY

KW - LIGAND-BINDING

KW - DRUG DISCOVERY

KW - CANCER-THERAPY

KW - POTENT

U2 - 10.1021/acschembio.6b00596

DO - 10.1021/acschembio.6b00596

M3 - Article

SN - 1554-8929

VL - 11

SP - 3310

EP - 3318

JO - ACS chemical biology

JF - ACS chemical biology

IS - 12

ER -

A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction

Abstract

Keywords

Access to Document

Handle.net

Datasets

CCDC 1054957: Experimental Crystal Structure Determination

CCDC 1054956: Experimental Crystal Structure Determination

CCDC 1054955: Experimental Crystal Structure Determination

Cite this