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Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy

View ORCID ProfileJoanna Zawacka-Pankau, Vera V. Grinkevich, Mikhail Burmakin, Aparna Vema, Karin Fawkner, Natalia Issaeva, Virginia Andreotti, Eleanor R. Dickinson, Elisabeth Hedström, Clemens Spinnler, Alberto Inga, Lars-Gunnar Larsson, Anders Karlén, Olga Tarasova, Vladimir Poroikov, Sergey Lavrenov, Maria Preobrazhenskaya, Perdita E. Barran, Andrei L. Okorokov, Galina Selivanova
doi: https://doi.org/10.1101/384248
Joanna Zawacka-Pankau
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Solnavägen 9, Stockholm, SE 171 65, Sweden
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  • ORCID record for Joanna Zawacka-Pankau
  • For correspondence: joannazawackapankau1@gmail.com
Vera V. Grinkevich
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Solnavägen 9, Stockholm, SE 171 65, Sweden
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Mikhail Burmakin
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Solnavägen 9, Stockholm, SE 171 65, Sweden
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Aparna Vema
2Division of Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, P.O. Box 574, BMC, S-751 23 Uppsala, Sweden
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Karin Fawkner
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Solnavägen 9, Stockholm, SE 171 65, Sweden
10Present address: TLV, Box 225 20, 104 22, Stockholm frame - the author has deceased during the project
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Natalia Issaeva
3Department of Otolaryngology, Yale Physicians Building, 800 Howard Ave, 4th Fl, New Haven, CT 06519
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Virginia Andreotti
4Unit of Molecular Mutagenesis and DNA repair, National Institute for Cancer Research, IST, L.go R. Benzi X, 16132 Genoa, Italy
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Eleanor R. Dickinson
5Manchester Institute of Biotechnology, The School of Chemistry, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK
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Elisabeth Hedström
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Solnavägen 9, Stockholm, SE 171 65, Sweden
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Clemens Spinnler
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Solnavägen 9, Stockholm, SE 171 65, Sweden
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Alberto Inga
6Centre for Integrative Biology, CIBIO, University of Trento, via Sommarive 9, 38123, Trento, Italy
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Lars-Gunnar Larsson
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Solnavägen 9, Stockholm, SE 171 65, Sweden
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Anders Karlén
2Division of Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, P.O. Box 574, BMC, S-751 23 Uppsala, Sweden
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Olga Tarasova
7Department for Bioinformatics, Institute of Biomedical Chemistry, 119121, Moscow, Russia
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Vladimir Poroikov
7Department for Bioinformatics, Institute of Biomedical Chemistry, 119121, Moscow, Russia
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Sergey Lavrenov
8Gause Institute of New Antibiotics, 119021, Moscow, Russia
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Maria Preobrazhenskaya
8Gause Institute of New Antibiotics, 119021, Moscow, Russia
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Perdita E. Barran
5Manchester Institute of Biotechnology, The School of Chemistry, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK
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Andrei L. Okorokov
9Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT, UK
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Galina Selivanova
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Solnavägen 9, Stockholm, SE 171 65, Sweden
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Abstract

Given the immense significance of p53 restoration for anti-cancer therapy, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in p53 regulation, whose targeting by RITA, PpIX and licofelone block the binding of p53 inhibitors, MDM2 and MDMX. Deletion and mutation analysis followed by molecular modeling, identified the key p53 residues S33 and S37 targeted by RITA and PpIX. We propose that the binding of small molecules to the identified site induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators. Our study provides the basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacological potential.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 07, 2018.
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Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy
Joanna Zawacka-Pankau, Vera V. Grinkevich, Mikhail Burmakin, Aparna Vema, Karin Fawkner, Natalia Issaeva, Virginia Andreotti, Eleanor R. Dickinson, Elisabeth Hedström, Clemens Spinnler, Alberto Inga, Lars-Gunnar Larsson, Anders Karlén, Olga Tarasova, Vladimir Poroikov, Sergey Lavrenov, Maria Preobrazhenskaya, Perdita E. Barran, Andrei L. Okorokov, Galina Selivanova
bioRxiv 384248; doi: https://doi.org/10.1101/384248
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Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy
Joanna Zawacka-Pankau, Vera V. Grinkevich, Mikhail Burmakin, Aparna Vema, Karin Fawkner, Natalia Issaeva, Virginia Andreotti, Eleanor R. Dickinson, Elisabeth Hedström, Clemens Spinnler, Alberto Inga, Lars-Gunnar Larsson, Anders Karlén, Olga Tarasova, Vladimir Poroikov, Sergey Lavrenov, Maria Preobrazhenskaya, Perdita E. Barran, Andrei L. Okorokov, Galina Selivanova
bioRxiv 384248; doi: https://doi.org/10.1101/384248

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