American Association for Cancer Research
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FGF401 characterizing data from FGF401, A First-In-Class Highly Selective and Potent FGFR4 Inhibitor for the Treatment of FGF19-Driven Hepatocellular Cancer

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posted on 2023-04-03, 15:25 authored by Andreas Weiss, Flavia Adler, Alexandra Buhles, Christelle Stamm, Robin A. Fairhurst, Michael Kiffe, Dario Sterker, Mario Centeleghe, Markus Wartmann, Jacqueline Kinyamu-Akunda, Heiko S. Schadt, Philippe Couttet, Armin Wolf, Youzhen Wang, Patrizia Barzaghi-Rinaudo, Masato Murakami, Audrey Kauffmann, Thomas Knoepfel, Nicole Buschmann, Catherine Leblanc, Robert Mah, Pascal Furet, Jutta Blank, Francesco Hofmann, William R. Sellers, Diana Graus Porta

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HCC

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ARTICLE ABSTRACT

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through the FGF19/FGFR4 axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3, and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic/pharmacodynamics/efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC90 value. FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a phase I/II study is currently ongoing in HCC and other solid malignancies.

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