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PDBsum entry 6v9c
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Transferase/transferase inhibitor
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PDB id
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6v9c
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References listed in PDB file
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Key reference
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Title
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Discovery of selective, Covalent fgfr4 inhibitors with antitumor activity in models of hepatocellular carcinoma.
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Authors
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H.Liu,
D.Niu,
R.T.Tham sjin,
A.Dubrovskiy,
Z.Zhu,
J.J.Mcdonald,
K.Fahnoe,
Z.Wang,
M.Munson,
A.Scholte,
M.Barrague,
M.Fitzgerald,
J.Liu,
M.Kothe,
F.Sun,
J.Murtie,
J.Ge,
J.Rocnik,
D.Harvey,
B.Ospina,
K.Perron,
G.Zheng,
E.Shehu,
L.A.D'Agostino.
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Ref.
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ACS Med Chem Lett, 2020,
11,
1899-1904.
[DOI no: ]
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PubMed id
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Abstract
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Hepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer
and is one of the most common forms of cancer worldwide. Aberrant signaling of
the FGF19-FGFR4 pathway leads to HCC in mice and is hypothesized to be a driver
in FGF19 amplified HCC in humans. Multiple small molecule inhibitors have been
pursued as targeted therapies for HCC in recent years, including several
selective FGFR4 inhibitors that are currently being evaluated in clinical
trials. Herein, we report a novel series of highly selective, covalent
2-amino-6,8-dimethyl-pyrido[2,3-d]pyrimidin-7(8H)-ones that
potently and selectively inhibit FGFR4 signaling through covalent modification
of Cys552, which was confirmed by X-ray crystallography. Correlative target
occupancy and pFGFR4 inhibition were observed in vivo, as well as tumor
regression in preclinical models of orthotopic and sorafenib-resistant HCC.
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