5KZI

Crystal structure of human Pim-1 kinase in complex with an imidazopyridazine inhibitor.

5KZI の概要

• エントリーDOI: 10.2210/pdb5kzi/pdb
• 分子名称: Serine/threonine-protein kinase pim-1, ~{N}-[4-[(3~{S})-3-azanylpiperidin-1-yl]pyridin-3-yl]-2-[2,6-bis(fluoranyl)phenyl]imidazo[1,5-b]pyridazin-7-amine (3 entities in total)
• 機能のキーワード: transferase, serine/threonine protein kinase, 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: 33485.87

構造登録者

Mohr, C. (登録日: 2016-07-25, 公開日: 2016-11-09, 最終更新日: 2024-03-06)

主引用文献

Wurz, R.P.,Sastri, C.,D'Amico, D.C.,Herberich, B.,Jackson, C.L.,Pettus, L.H.,Tasker, A.S.,Wu, B.,Guerrero, N.,Lipford, J.R.,Winston, J.T.,Yang, Y.,Wang, P.,Nguyen, Y.,Andrews, K.L.,Huang, X.,Lee, M.R.,Mohr, C.,Zhang, J.D.,Reid, D.L.,Xu, Y.,Zhou, Y.,Wang, H.L.
Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors.
Bioorg. Med. Chem. Lett., 26:5580-5590, 2016

PubMed Abstract: High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC values of 0.024nM and 0.095nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC=28nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication.

PubMed: 27769621
DOI: 10.1016/j.bmcl.2016.09.067

実験手法

X-RAY DIFFRACTION (2.1 Å)