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Rotational Freedom, Steric Hindrance, and Protein Dynamics Explain BLU554 Selectivity for the Hinge Cysteine of FGFR4

Xiaojing Lin1, Yuliana Yosaatmadja1, Maria Kalyukina1

  • 1School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

ACS Medicinal Chemistry Letters
|August 16, 2019
PubMed

Insights

Aberrant FGFR4 signaling drives hepatocellular carcinoma (HCC). Researchers developed selective FGFR4 inhibitors, like BLU554, targeting a unique cysteine residue for effective cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Structural Biology

Background:

  • Aberrant Fibroblast Growth Factor Receptor 4 (FGFR4) signaling is implicated in hepatocellular carcinoma (HCC) pathogenesis.
  • FGFR4 represents a promising therapeutic target for a subset of HCC patients.

Purpose of the Study:

  • To characterize the selectivity and reactivity of covalent FGFR4 inhibitors.
  • To elucidate the structural basis for selective FGFR4 inhibition by BLU554.

Main Methods:

  • Mass spectrometry assays were employed to assess inhibitor reactivity.
  • Cocrystal structures of FGFR4 and FGFR1 in complex with inhibitors were determined.
  • Inhibitor selectivity profiles were evaluated.

Main Results:

  • BLU554 demonstrated selective covalent inhibition of FGFR4 by targeting a poorly conserved cysteine residue.
  • Cocrystal structures revealed the molecular interactions governing inhibitor binding.
  • Off-target binding to FGFR1 was observed through an alternative conformation, highlighting selectivity determinants.

Conclusions:

  • The study elucidates the structural mechanisms underlying BLU554's exceptional selectivity for FGFR4.
  • Understanding these mechanisms is crucial for developing targeted therapies for FGFR4-driven cancers.
  • Rotational freedom, steric hindrance, and protein dynamics contribute to FGFR4-specific covalent inhibition.

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