PDBsum entry 6v9c

Transferase/transferase inhibitor

PDB id: 6v9c

Contents

Protein chain

279 a.a.

Ligands

QS7

SO4 ×2

Waters ×165

PDB id:

6v9c

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of fgfr4 kinase domain in complex with covalent inhibitor

Structure:

Fibroblast growth factor receptor 4. Chain: a. Synonym: fgfr-4. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfr4, jtk2, tkf. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.90Å R-factor: 0.201 R-free: 0.227

Authors:

J.Liu,H.Liu

Key ref:

H.Liu et al. (2020). Discovery of Selective, Covalent FGFR4 Inhibitors with Antitumor Activity in Models of Hepatocellular Carcinoma. ACS Med Chem Lett, 11, 1899-1904. PubMed id: 33062171 DOI: 10.1021/acsmedchemlett.9b00601

Date:

13-Dec-19 Release date: 25-Mar-20

Protein chain

P22455  (FGFR4_HUMAN) -  Fibroblast growth factor receptor 4 from Homo sapiens

Seq: 802 a.a.

Struc: 279 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/acsmedchemlett.9b00601

ACS Med Chem Lett 11:1899-1904 (2020)

PubMed id: 33062171

Discovery of Selective, Covalent FGFR4 Inhibitors with Antitumor Activity in Models of Hepatocellular Carcinoma.

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.

ABSTRACT

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.