4K18

Structure of PIM-1 kinase bound to 5-(4-cyanobenzyl)-N-(4-fluorophenyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxamide

4K18 の概要

• エントリーDOI: 10.2210/pdb4k18/pdb
• 関連するPDBエントリー: 4K0Y 4K1B
• 分子名称: Serine/threonine-protein kinase pim-1, PHOSPHATE ION, 5-(4-cyanobenzyl)-N-(4-fluorophenyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: pim-1, kinase domain, ser/thr kinase, atp-competitive, structure-based drug design, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32416.56

構造登録者

Murray, J.M.,Wallweber, H.,Steffek, M. (登録日: 2013-04-04, 公開日: 2013-05-15, 最終更新日: 2024-02-28)

主引用文献

Wang, X.,Magnuson, S.,Pastor, R.,Fan, E.,Hu, H.,Tsui, V.,Deng, W.,Murray, J.,Steffek, M.,Wallweber, H.,Moffat, J.,Drummond, J.,Chan, G.,Harstad, E.,Ebens, A.J.
Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design.
Bioorg.Med.Chem.Lett., 23:3149-3153, 2013

PubMed Abstract: Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms.

PubMed: 23623490
DOI: 10.1016/j.bmcl.2013.04.020

実験手法

X-RAY DIFFRACTION (2.051 Å)