2. Academic Validation
  3. Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles

Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles

  • J Med Chem. 2024 Apr 25;67(8):6549-6569. doi: 10.1021/acs.jmedchem.3c02483.
Moritz Schwarz 1,  Maksym Kurkunov 1 2,  Florian Wittlinger 1,  Ramona Rudalska 2 3,  Guiqun Wang 4 5 6,  Martin Peter Schwalm 4 5 6,  Alexander Rasch 1,  Benedikt Wagner 1 2,  Stefan A Laufer 1 2 7,  Stefan Knapp 4 5 6,  Daniel Dauch 2 3 7,  Matthias Gehringer 1 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
  • 2 Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany.
  • 3 Department of Medical Oncology and Pneumology, University Hospital Tübingen, 72076 Tübingen, Germany.
  • 4 German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 5 Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von Laue Str. 15, 60438 Frankfurt am Main, Germany.
  • 6 Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von Laue Str. 9, 60438 Frankfurt am Main, Germany.
  • 7 Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tübingen, Germany.
PMID: 38604131 DOI: 10.1021/acs.jmedchem.3c02483
Abstract

Fibroblast Growth Factor receptor 4 (FGFR4) is thought to be a driver in several Cancer types, most notably in hepatocellular carcinoma. One way to achieve high potency and isoform selectivity for FGFR4 is covalently targeting a rare cysteine (C552) in the hinge region of its kinase domain that is not present in other FGFR family members (FGFR1-3). Typically, this cysteine is addressed via classical acrylamide electrophiles. We demonstrate that noncanonical covalent "warheads" based on nucleophilic aromatic substitution (SNAr) chemistry can be employed in a rational manner to generate highly potent and (isoform-)selective FGFR4 inhibitors with a low intrinsic reactivity. Key compounds showed low to subnanomolar potency, efficient covalent inactivation kinetics, and excellent selectivity against the other FGFRs, the kinases with an equivalent cysteine, and a representative subset of the kinome. Moreover, these compounds achieved nanomolar potencies in cellular assays and demonstrated good microsomal stability, highlighting the potential of SNAr-based approaches in covalent inhibitor design.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-158248
    FGFR4抑制剂
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