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

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 residu...

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Published inACS medicinal chemistry letters Vol. 10; no. 8; pp. 1180 - 1186
Main Authors Lin, Xiaojing, Yosaatmadja, Yuliana, Kalyukina, Maria, Middleditch, Martin J, Zhang, Zhen, Lu, Xiaoyun, Ding, Ke, Patterson, Adam V, Smaill, Jeff B, Squire, Christopher J
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 08.08.2019
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Summary: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.
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ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.9b00196