4TY1

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

4TY1 の概要

• エントリーDOI: 10.2210/pdb4ty1/pdb
• 分子名称: Serine/threonine-protein kinase pim-1, N-tert-butyl-5-[3-(4-cyclopropylpyrimidin-2-yl)-1H-indol-5-yl]-1,3,4-oxadiazol-2-amine, GLYCEROL, ... (4 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: 33530.95

構造登録者

Mohr, C. (登録日: 2014-07-07, 公開日: 2015-02-04, 最終更新日: 2023-12-27)

主引用文献

Wurz, R.P.,Pettus, L.H.,Jackson, C.,Wu, B.,Wang, H.L.,Herberich, B.,Cee, V.,Lanman, B.A.,Reed, A.B.,Chavez, F.,Nixey, T.,Laszlo, J.,Wang, P.,Nguyen, Y.,Sastri, C.,Guerrero, N.,Winston, J.,Lipford, J.R.,Lee, M.R.,Andrews, K.L.,Mohr, C.,Xu, Y.,Zhou, Y.,Reid, D.L.,Tasker, A.S.
The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors.
Bioorg.Med.Chem.Lett., 25:847-855, 2015

PubMed Abstract: High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole-thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compound's potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (Ki values of 0.55nM and 0.28nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50=150nM). This compound had moderate clearance and bioavailability in rat (CL=2.42L/kg/h; %F=24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74μM (18μg/mL) when dosed at 10, 30, 100 and 200mg/kg po in mice.

PubMed: 25599837
DOI: 10.1016/j.bmcl.2014.12.067

実験手法

X-RAY DIFFRACTION (2.7 Å)