8UDT

The X-RAY co-crystal structure of human FGFR3 and KIN-3248

8UDT の概要

• エントリーDOI: 10.2210/pdb8udt/pdb
• 分子名称: Fibroblast growth factor receptor 3, D-MALATE, 3-[(1-cyclopropyl-4,6-difluoro-1H-benzimidazol-5-yl)ethynyl]-1-[(3R,5R)-5-(methoxymethyl)-1-propanoylpyrrolidin-3-yl]-5-(methylamino)-1H-pyrazole-4-carboxamide, ... (4 entities in total)
• 機能のキーワード: fgfr inhibitor, covalent drug, kin-3248, alteration, mutation, structure-based drug design, kinase inhibitor, signaling, proliferation, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 103070.87

構造登録者

Tyhonas, J.S.,Arnold, L.D.,Cox, J.,Franovic, A.,Gardiner, E.,Grandinetti, K.,Kania, R.,Kanouni, T.,Lardy, M.,Li, C.,Martin, E.S.,Miller, N.,Mohan, A.,Murphy, E.A.,Perez, M.,Soroceanu, L.,Timple, N.,Uryu, S.,Womble, S.,Kaldor, S.W. (登録日: 2023-09-29, 公開日: 2024-02-07, 最終更新日: 2024-11-06)

主引用文献

Tyhonas, J.S.,Arnold, L.D.,Cox, J.M.,Franovic, A.,Gardiner, E.,Grandinetti, K.,Kania, R.,Kanouni, T.,Lardy, M.,Li, C.,Martin, E.S.,Miller, N.,Mohan, A.,Murphy, E.A.,Perez, M.,Soroceanu, L.,Timple, N.,Uryu, S.,Womble, S.,Kaldor, S.W.
Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations.
J.Med.Chem., 67:1734-1746, 2024

PubMed Abstract: Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients. Genomic profiling of tumors refractory to current FGFR inhibitors in the clinic has revealed several acquired driver alterations that could be the target of next generation therapeutics. Herein, we describe how structure-based drug design (SBDD) was used to enable the discovery of the potent and kinome selective pan-FGFR inhibitor , which is active against many acquired resistance mutations. is currently in phase I clinical development for the treatment of advanced tumors harboring FGFR2 and/or FGFR3 gene alterations.

PubMed: 38267212
DOI: 10.1021/acs.jmedchem.3c01819

実験手法

X-RAY DIFFRACTION (2.829 Å)