Open AccessRotational Freedom, Steric Hindrance, and Protein Dynamics Explain BLU554 Selectivity for the Hinge Cysteine of FGFR4
Author(s) -
Xiaojing Lin,
Y. Yosaatmadja,
Maria Kalyukina,
Martin Middleditch,
Zhen Zhang,
Xiaoyun Lu,
Ke Ding,
Adam V. Patterson,
Jeff B. Smaill,
C.J. Squire
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00196
Subject(s) - steric effects , cysteine , chemistry , covalent bond , selectivity , combinatorial chemistry , biochemistry , stereochemistry , organic chemistry , enzyme , catalysis
Aberration in FGFR4 signaling drives carcinogenesis and progression in a subset of hepatocellular carcinoma (HCC) patients, thereby making FGFR4 an attractive molecular target for this disease. Selective FGFR4 inhibition can be achieved through covalently targeting a poorly conserved cysteine residue in the FGFR4 kinase domain. We report mass spectrometry assays and cocrystal structures of FGFR4 in covalent complex with the clinical candidate BLU554 and with a series of four structurally related inhibitors that define the inherent reactivity and selectivity profile of these molecules. We further reveal the structure of FGFR1 with one of our inhibitors and show that off-target covalent binding can occur through an alternative conformation that supports targeting of a cysteine conserved in all members of the FGFR family. Collectively, we propose that rotational freedom, steric hindrance, and protein dynamics explain the exceptional selectivity profile of BLU554 for targeting FGFR4.