5TD2

Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate

5TD2 の概要

• エントリーDOI: 10.2210/pdb5td2/pdb
• 分子名称: Tyrosine-protein kinase Mer, N-[2-{4-[(2S)-4-(methylsulfonyl)morpholin-2-yl]-1,3-thiazol-2-yl}-4-(morpholin-4-yl)phenyl]-1H-imidazole-2-carboxamide (3 entities in total)
• 機能のキーワード: kinase, inhibitor, surrogate, oncology, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Membrane ; Single-pass type I membrane protein : Q12866
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66158.89

構造登録者

Hoffman, I.D.,Lawson, J.D. (登録日: 2016-09-16, 公開日: 2017-01-25, 最終更新日: 2024-03-06)

主引用文献

Keung, W.,Boloor, A.,Brown, J.,Kiryanov, A.,Gangloff, A.,Lawson, J.D.,Skene, R.,Hoffman, I.,Atienza, J.,Kahana, J.,De Jong, R.,Farrell, P.,Balakrishna, D.,Halkowycz, P.
Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate.
Bioorg. Med. Chem. Lett., 27:1099-1104, 2017

PubMed Abstract: Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.

PubMed: 28082036
DOI: 10.1016/j.bmcl.2016.12.024

実験手法

X-RAY DIFFRACTION (2.68 Å)