2. Academic Validation
  3. Tetrahydropyridine LIMK inhibitors: Structure activity studies and biological characterization

Tetrahydropyridine LIMK inhibitors: Structure activity studies and biological characterization

  • Eur J Med Chem. 2024 Apr 9:271:116391. doi: 10.1016/j.ejmech.2024.116391.
Anthony Champiré 1,  Rayan Berabez 1,  Abdennour Braka 1,  Aurélie Cosson 2,  Justine Corret 2,  Caroline Girardin 2,  Amandine Serrano 2,  Samia Aci-Sèche 1,  Pascal Bonnet 1,  Béatrice Josselin 3,  Pierre Brindeau 3,  Sandrine Ruchaud 3,  Rémy Leguevel 4,  Deep Chatterjee 5,  Sebastian Mathea 5,  Stefan Knapp 5,  Régis Brion 6,  Franck Verrecchia 7,  Béatrice Vallée 2,  Karen Plé 1,  Hélène Bénédetti 8,  Sylvain Routier 9
Affiliations

Affiliations

  • 1 ICOA, Université d'Orléans, CNRS UMR 7311, 45067, Orléans, France.
  • 2 Centre de Biophysique Moléculaire, CNRS UPR4301, 45071, Orléans, France.
  • 3 Sorbonne Université / CNRS UMR 8227, Station Biologique, 29688, Roscoff, France.
  • 4 Plate-forme ImPACcell, UAR BIOSIT, Université de Rennes 1, 35043, Rennes, France.
  • 5 Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences Goethe- University, 60438, Frankfurt am Main, Germany; Institute for Pharmaceutical Chemistry, Max von Lauestrasse 9, Goethe-University, 60438, Frankfurt am Main, Germany.
  • 6 CRCI(2)NA, INSERM, UMR 1307, CNRS, UMR 6075, Université de Nantes, 44035, Nantes, France; Centre Hospitalier Universitaire de Nantes, 44000, Nantes, France.
  • 7 CRCI(2)NA, INSERM, UMR 1307, CNRS, UMR 6075, Université de Nantes, 44035, Nantes, France.
  • 8 Centre de Biophysique Moléculaire, CNRS UPR4301, 45071, Orléans, France. Electronic address: helene.benedetti@cnrs.fr.
  • 9 ICOA, Université d'Orléans, CNRS UMR 7311, 45067, Orléans, France. Electronic address: sylvain.routier@univ-orleans.fr.
PMID: 38669909 DOI: 10.1016/j.ejmech.2024.116391
Abstract

LIM Kinases, LIMK1 and LIMK2, have become promising targets for the development of inhibitors with potential application for the treatment of several major diseases. LIMKs play crucial roles in Cytoskeleton remodeling as downstream effectors of small G proteins of the Rho-GTPase family, and as major regulators of cofilin, an actin depolymerizing factor. In this article we describe the conception, synthesis, and biological evaluation of novel tetrahydropyridine pyrrolopyrimidine LIMK inhibitors. Homology models were first constructed to better understand the binding mode of our preliminary compounds and to explain differences in biological activity. A library of over 60 products was generated and in vitro enzymatic activities were measured in the mid to low nanomolar range. The most promising derivatives were then evaluated in cell on cofilin phosphorylation inhibition which led to the identification of 52 which showed excellent selectivity for LIMKs in a kinase selectivity panel. We also demonstrated that 52 affected the cell Cytoskeleton by disturbing actin filaments. Cell migration studies with this derivative using three different cell lines displayed a significant effect on cell motility. Finally, the crystal structure of the kinase domain of LIMK2 complexed with 52 was solved, greatly improving our understanding of the interaction between 52 and LIMK2 active site. The reported data represent a basis for the development of more efficient LIMK inhibitors for future in vivo preclinical validation.

Keywords

Cell migration; Co-crystallization; Cofilin; Cytoskeleton; Kinase; LIMK inhibitors; Molecular modeling; Synthesis.

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