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Kessler D, Mayer M, Zahn SK, et al. Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods. ChemMedChem. 2021;16(9):1420-1424doi: 10.1002/cmdc.202000839.
Kessler, D., Mayer, M., Zahn, S. K., Zeeb, M., Wöhrle, S., Bergner, A., Bruchhaus, J., Ciftci, T., Dahmann, G., Dettling, M., Döbel, S., Fuchs, J. E., Geist, L., Hela, W., Kofink, C., Kousek, R., Moser, F., Puchner, T., Rumpel, K., Scharnweber, M., Werni, P., Wolkerstorfer, B., Breitsprecher, D., Baaske, P., Pearson, M., McConnell, D. B., & Böttcher, J. (2021). Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods. ChemMedChem, 16(9), 1420-1424. https://doi.org/10.1002/cmdc.202000839
Kessler, Dirk, et al. "Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods." ChemMedChem vol. 16,9 (2021): 1420-1424. doi: https://doi.org/10.1002/cmdc.202000839
Kessler D, Mayer M, Zahn SK, Zeeb M, Wöhrle S, Bergner A, Bruchhaus J, Ciftci T, Dahmann G, Dettling M, Döbel S, Fuchs JE, Geist L, Hela W, Kofink C, Kousek R, Moser F, Puchner T, Rumpel K, Scharnweber M, Werni P, Wolkerstorfer B, Breitsprecher D, Baaske P, Pearson M, McConnell DB, Böttcher J. Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods. ChemMedChem. 2021 May 06;16(9):1420-1424. doi: 10.1002/cmdc.202000839. Epub 2021 Jan 14. PMID: 33275320; PMCID: PMC8247886.
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ChemMedChem. 2021 May 06;16(9):1420-1424. doi: 10.1002/cmdc.202000839. Epub 2021 Jan 14.

Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods.

ChemMedChem

Dirk Kessler, Moriz Mayer, Stephan K Zahn, Markus Zeeb, Simon Wöhrle, Andreas Bergner, Jens Bruchhaus, Tuncay Ciftci, Georg Dahmann, Maike Dettling, Sandra Döbel, Julian E Fuchs, Leonhard Geist, Wolfgang Hela, Christiane Kofink, Roland Kousek, Franziska Moser, Teresa Puchner, Klaus Rumpel, Maximilian Scharnweber, Patrick Werni, Bernhard Wolkerstorfer, Dennis Breitsprecher, Philipp Baaske, Mark Pearson, Darryl B McConnell, Jark Böttcher

Affiliations

  1. Boehringer Ingelheim RCV GmbH & Co KG, Dr.-Boehringer-Gasse 5-11, 1121, Vienna, Austria.
  2. Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Straße 65, 88397, Biberach, Germany.
  3. NanoTemper Technologies GmbH, Floessergasse 4, 81369, Muenchen, Germany.
  4. Leica Microsystems AG, Max Schmidheiny-Strasse 201, 9435, Heerbrugg, Switzerland.

PMID: 33275320 PMCID: PMC8247886 DOI: 10.1002/cmdc.202000839

Abstract

Aberrant WNT pathway activation, leading to nuclear accumulation of β-catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of β-catenin and subsequent nuclear translocation. Restoring cellular degradation of β-catenin represents a potential therapeutic strategy. Here, we report the fragment-based discovery of a small molecule binder to β-catenin, including the structural elucidation of the binding mode by X-ray crystallography. The difficulty in drugging β-catenin was confirmed as the primary screening campaigns identified only few and very weak hits. Iterative virtual and NMR screening techniques were required to discover a compound with sufficient potency to be able to obtain an X-ray co-crystal structure. The binding site is located between armadillo repeats two and three, adjacent to the BCL9 and TCF4 binding sites. Genetic studies show that it is unlikely to be useful for the development of protein-protein interaction inhibitors but structural information and established assays provide a solid basis for a prospective optimization towards β-catenin proteolysis targeting chimeras (PROTACs) as alternative modality.

© 2020 The Authors. ChemMedChem published by Wiley-VCH GmbH.

Keywords: PROTAC; WaterLOGSY; fragment-based screening; microscale thermophoresis; β-catenin

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