Discovery of Selective, Covalent FGFR4 Inhibitors with Antitumor Activity in Models of Hepatocellular Carcinoma
| Autor: | Andrew Scholte, Jinyu Liu, Maria Fitzgerald, Jie Ge, D. Niu, Haibo Liu, Beatriz Ospina, Michael Kothe, Laura Akullian D’Agostino, Joshua Murtie, Gang Zheng, Fangxian Sun, Elvis Shehu, Zhendong Zhu, Mcdonald Joseph John, Matthieu Barrague, Kelly Fahnoe, Darren Harvey, Mark Munson, Zhigang Wang, Jennifer Rocnik, Robert Tjin Tham Sjin, Keli Perron, Alex Dubrovskiy |
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| Rok vydání: | 2019 |
| Předmět: |
Antitumor activity
010405 organic chemistry business.industry Organic Chemistry Cancer FGF19 Fibroblast growth factor receptor 4 medicine.disease 01 natural sciences Biochemistry Small molecule digestive system diseases 0104 chemical sciences 010404 medicinal & biomolecular chemistry In vivo Covalent bond Hepatocellular carcinoma Drug Discovery medicine Cancer research business |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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