5B7V

Human FGFR1 kinase in complex with CH5183284

「3WJ6」から置き換えられました

5B7V の概要

• エントリーDOI: 10.2210/pdb5b7v/pdb
• 分子名称: Fibroblast growth factor receptor 1, [5-amino-1-(2-methyl-1H-benzimidazol-6-yl)-1H-pyrazol-4-yl](1H-indol-2-yl)methanone, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: protein kinase, atp-binding, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein: P11362
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71426.05

構造登録者

Fukami, T.A.,Lukacs, C.M.,Janson, C. (登録日: 2016-06-09, 公開日: 2016-06-22, 最終更新日: 2023-11-08)

主引用文献

Nakanishi, Y.,Akiyama, N.,Tsukaguchi, T.,Fujii, T.,Sakata, K.,Sase, H.,Isobe, T.,Morikami, K.,Shindoh, H.,Mio, T.,Ebiike, H.,Taka, N.,Aoki, Y.,Ishii, N.
The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor
Mol.Cancer Ther., 13:2547-2558, 2014

PubMed Abstract: The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clinical benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F-driven tumor growth. CH5183284/Debio 1347 is under clinical investigation for the treatment of patients harboring FGFR genetic alterations.

PubMed: 25169980
DOI: 10.1158/1535-7163.MCT-14-0248

実験手法

X-RAY DIFFRACTION (2.15 Å)