p21-Activated Kinase (PAK) Group I-Targeting Inhibitors Promote the Dimeric Conformation in Live Cells

  • ACS Chem Biol. 2026 Jun 13. doi: 10.1021/acschembio.6c00410.
Theresa A L Ehret  1  2 ,  Benedict-Tilman Berger  1  2 ,  Nicolai Raig  1  2 ,  Felix Nowotka  1 ,  Neele Manik  1 ,  Viktoria Morasch  1  2 ,  Andreas Krämer  1  2 ,  Lewis Elson  1  2 ,  Thiago Loreto Matos  3 ,  Susanne Müller  1  2 ,  Stefan Knapp  1  2  4 ,  Martin P Schwalm  1  2  4
Affiliations
  • 1. Institut für Pharmazeutische Chemie, Goethe-University Frankfurt, Biozentrum, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 2. Structural Genomics Consortium, Goethe-University Frankfurt, Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 3. Pharmacogenetics Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza 60430-160, Brazil.
  • 4. German Translational Cancer Consortium (DKTK)/German Cancer Research Center (DKFZ), DKTK Site Frankfurt-Mainz, 69120 Heidelberg, Germany.
PMID: 42287201 DOI: 10.1021/acschembio.6c00410
Abstract

p21-activated kinases (PAKs) are involved in a broad range of cellular processes and are emerging drug targets. The human PAK family consists of 6 kinases, divided into group I (PAK1-3) and group II (PAK4-6), both families are regulated by distinct activation mechanisms and interaction partners. Currently, there are no assays available enabling the study of on-target activity for all PAK isoforms in cells. To this end, we developed a series of NanoLuc- and HaloTag-based bioluminescence resonance energy transfer assays to quantify inhibitor target engagement and dimerization of PAK isoforms in living cells. Interestingly, we found evidence that inhibitors might promote the formation of group I PAK dimers. Thus, our data uncovered a live-cell mechanism by which inhibitors modulate this dimeric conformation and provide new tools for future PAK Inhibitor design.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-184447
    RN193
    PAK Inhibitor
    target: PAK
    Research Areas: Others