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Structure-Kinetic-Relationship Reveals the Mechanism of Selectivity of FAK Inhibitors Over PYK2

53 Pages Posted: 14 Aug 2020 Publication Status: Published

See all articles by Benedict-Tilman Berger

Benedict-Tilman Berger

Goethe University Frankfurt - Structural Genomics Consortium

Marta Amaral

Merck KGaA - Discovery Technologies

Daria B. Kokh

Heidelberg Institute for Theoretical Studies (HITS) - Molecular and Cellular Modeling Group

Ariane Nunes-Alves

Heidelberg Institute for Theoretical Studies (HITS) - Molecular and Cellular Modeling Group

Djordje Musil

Merck KGaA - Discovery Technologies

Timo Heinrich

Merck KGaA - Discovery Technologies

Martin Schröder

Goethe University Frankfurt - Institute of Pharmaceutical Chemistry

Rebecca Neil

Heidelberg Institute for Theoretical Studies (HITS) - Molecular and Cellular Modeling Group

Jing Wang

University of Oxford - Structural Genomics Consortium (SGC)

Iva Navratilova

University of Dundee - Division of Biological Chemistry and Drug Discovery

Joerg Bomke

Merck KGaA - Discovery Technologies

Jonathan M. Elkins

University of Oxford - Structural Genomics Consortium (SGC)

Susanne Müller

Goethe University Frankfurt - Structural Genomics Consortium

Matthias Frech

Merck KGaA - Discovery Technologies

Rebecca C. Wade

Heidelberg Institute for Theoretical Studies (HITS) - Molecular and Cellular Modeling Group

Stefan Knapp

Goethe University Frankfurt - Institute of Pharmaceutical Chemistry

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Abstract

There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rational for kinetic selectivity between two closely related kinases: Focal Adhesion Kinase (FAK) and Proline-rich Tyrosine Kinase 2 (PYK2). We found that slow off-rate FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG helical region providing a structural rational for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlated well with computed relative residence times from molecular simulations providing a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2.

Suggested Citation

Berger, Benedict-Tilman and Amaral, Marta and Kokh, Daria B. and Nunes-Alves, Ariane and Musil, Djordje and Heinrich, Timo and Schröder, Martin and Neil, Rebecca and Wang, Jing and Navratilova, Iva and Bomke, Joerg and Elkins, Jonathan M. and Müller, Susanne and Frech, Matthias and Wade, Rebecca C. and Knapp, Stefan, Structure-Kinetic-Relationship Reveals the Mechanism of Selectivity of FAK Inhibitors Over PYK2. Available at SSRN: https://ssrn.com/abstract=3656604 or http://dx.doi.org/10.2139/ssrn.3656604
This version of the paper has not been formally peer reviewed.

Benedict-Tilman Berger

Goethe University Frankfurt - Structural Genomics Consortium ( email )

Grüneburgplatz 1
Frankfurt am Main, 60323
Germany

Marta Amaral

Merck KGaA - Discovery Technologies ( email )

Daria B. Kokh

Heidelberg Institute for Theoretical Studies (HITS) - Molecular and Cellular Modeling Group ( email )

Schloss-Wolfsbrunnenweg 35
Heidelberg, D-69118
Germany

Ariane Nunes-Alves

Heidelberg Institute for Theoretical Studies (HITS) - Molecular and Cellular Modeling Group ( email )

Schloss-Wolfsbrunnenweg 35
Heidelberg, D-69118
Germany

Djordje Musil

Merck KGaA - Discovery Technologies ( email )

Timo Heinrich

Merck KGaA - Discovery Technologies

Martin Schröder

Goethe University Frankfurt - Institute of Pharmaceutical Chemistry

Max-von-Laue-Str. 9
Frankfurt, D-60438
Germany

Rebecca Neil

Heidelberg Institute for Theoretical Studies (HITS) - Molecular and Cellular Modeling Group ( email )

Schloss-Wolfsbrunnenweg 35
Heidelberg, D-69118
Germany

Jing Wang

University of Oxford - Structural Genomics Consortium (SGC) ( email )

Roosevelt Drive
Old Road Campus Research Building
Oxford, England OX3 7DQ
United Kingdom

Iva Navratilova

University of Dundee - Division of Biological Chemistry and Drug Discovery ( email )

Dundee, Scotland DD1 4HN
United Kingdom

Joerg Bomke

Merck KGaA - Discovery Technologies ( email )

Jonathan M. Elkins

University of Oxford - Structural Genomics Consortium (SGC) ( email )

Roosevelt Drive
Old Road Campus Research Building
Oxford, England OX3 7DQ
United Kingdom

Susanne Müller

Goethe University Frankfurt - Structural Genomics Consortium ( email )

Grüneburgplatz 1
Frankfurt am Main, 60323
Germany

Matthias Frech

Merck KGaA - Discovery Technologies ( email )

Rebecca C. Wade

Heidelberg Institute for Theoretical Studies (HITS) - Molecular and Cellular Modeling Group ( email )

Schloss-Wolfsbrunnenweg 35
Heidelberg, D-69118
Germany

Stefan Knapp (Contact Author)

Goethe University Frankfurt - Institute of Pharmaceutical Chemistry ( email )

Max-von-Laue-Str. 9
Frankfurt, D-60438
Germany

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