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Novel Allosteric Mechanism of P53 Activation by Small Molecules for Targeted Anticancer Therapy

65 Pages Posted: 2 Nov 2018 Sneak Peek Status: Under Review

See all articles by Joanna Zawacka-Pankau

Joanna Zawacka-Pankau

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Vera V. Grinkevich

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Mikhail Burmakin

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Aparna Vema

Uppsala University - Division of Organic Pharmaceutical Chemistry

Karin Ridderstråle

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Natalia Issaeva

Yale Physicians Building - Department of Otolaryngology

Virginia Andreotti

National Institute for Cancer Research - Unit of Molecular Mutagenesis and DNA repair

Eleanor R. Dickinson

University of Manchester - The Manchester Institute of Biotechnology

Elisabeth Hedström

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Clemens Spinnler

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Alberto Inga

University of Trento - Centre for Integrative Biology (CIBIO)

Lars-Gunnar Larsson

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Anders Karlén

Uppsala University - Division of Organic Pharmaceutical Chemistry

Olga Tarasova

Institute of Biomedical Chemistry

Vladimir Poroikov

Institute of Biomedical Chemistry

Sergey Lavrenov

Institute of Biomedical Chemistry

Maria Preobrazhenskaya

Gause Institute of New Antibiotics

Margareta Wilhelm

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Perdita E. Barran

University of Manchester - The Manchester Institute of Biotechnology

Andrei L. Okorokov

Gause Institute of New Antibiotics

Galina Selivanova

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

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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 a 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 blocks the binding of p53 inhibitors, MDM2 and MDMX. Deletion and mutation analysis followed by molecular modelling, 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 basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacological potential.

Suggested Citation

Zawacka-Pankau, Joanna and Grinkevich, Vera V. and Burmakin, Mikhail and Vema, Aparna and Ridderstråle, Karin and Issaeva, Natalia and Andreotti, Virginia and Dickinson, Eleanor R. and Hedström, Elisabeth and Spinnler, Clemens and Inga, Alberto and Larsson, Lars-Gunnar and Karlén, Anders and Tarasova, Olga and Poroikov, Vladimir and Lavrenov, Sergey and Preobrazhenskaya, Maria and Wilhelm, Margareta and Barran, Perdita E. and Okorokov, Andrei L. and Selivanova, Galina, Novel Allosteric Mechanism of P53 Activation by Small Molecules for Targeted Anticancer Therapy (October 30, 2018). Available at SSRN: https://ssrn.com/abstract=3275278 or http://dx.doi.org/10.2139/ssrn.3275278
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Joanna Zawacka-Pankau (Contact Author)

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC) ( email )

Solnavägen 9
Solna, 171 65
Sweden

Vera V. Grinkevich

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Solnavägen 9
Solna, 171 65
Sweden

Mikhail Burmakin

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Solnavägen 9
Solna, 171 65
Sweden

Aparna Vema

Uppsala University - Division of Organic Pharmaceutical Chemistry

P.O. Box 574
BMC
S-751 23 Uppsala
Sweden

Karin Ridderstråle

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Solnavägen 9
Solna, 171 65
Sweden

Natalia Issaeva

Yale Physicians Building - Department of Otolaryngology

800 Howard Ave, 4th Fl
New Haven, CT 06519
United States

Virginia Andreotti

National Institute for Cancer Research - Unit of Molecular Mutagenesis and DNA repair

IST, L.go R. Benzi X
16132 Genoa
Italy

Eleanor R. Dickinson

University of Manchester - The Manchester Institute of Biotechnology

131 Princess St
Manchester, M1 7DN
United Kingdom

Elisabeth Hedström

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Solnavägen 9
Solna, 171 65
Sweden

Clemens Spinnler

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Solnavägen 9
Solna, 171 65
Sweden

Alberto Inga

University of Trento - Centre for Integrative Biology (CIBIO)

via Sommarive n. 9, Povo (TN)
Povo, Trentino 38123
Italy

Lars-Gunnar Larsson

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Solnavägen 9
Solna, 171 65
Sweden

Anders Karlén

Uppsala University - Division of Organic Pharmaceutical Chemistry

P.O. Box 574
BMC
S-751 23 Uppsala
Sweden

Olga Tarasova

Institute of Biomedical Chemistry

Moscow, 119121
Russia

Vladimir Poroikov

Institute of Biomedical Chemistry

Moscow, 119121
Russia

Sergey Lavrenov

Institute of Biomedical Chemistry

Moscow, 119121
Russia

Maria Preobrazhenskaya

Gause Institute of New Antibiotics

Moscow, 119021
Russia

Margareta Wilhelm

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC)

Solnavägen 9
Solna, 171 65
Sweden

Perdita E. Barran

University of Manchester - The Manchester Institute of Biotechnology

131 Princess St
Manchester, M1 7DN
United Kingdom

Andrei L. Okorokov

Gause Institute of New Antibiotics

Moscow, 119021
Russia

Galina Selivanova

Karolinska Institutet - Department of Microbiology, Tumor and Cell Biology (MTC) ( email )

Solnavägen 9
Solna, 171 65
Sweden

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