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
  • 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.

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