4BZN

Crystal structure of PIM1 in complex with a Pyrrolo(1,2-a)Pyrazinone inhibitor

4BZN の概要

• エントリーDOI: 10.2210/pdb4bzn/pdb
• 関連するPDBエントリー: 4BZO
• 分子名称: SERINE/THREONINE-PROTEIN KINASE PIM-1, N-(2,2-dimethylpropyl)-2-[1-oxo-7-(thiophen-3-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]acetamide (3 entities in total)
• 機能のキーワード: pim1, atp binding, kinase inhibitor, transferase
• 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: 36181.15

構造登録者

Casale, E.,Casuscelli, F.,Ardini, E.,Avanzi, N.,Cervi, G.,D'Anello, M.,Donati, D.,Faiardi, D.,Ferguson, R.D.,Fogliatto, G.,Galvani, A.,Marsiglio, A.,Mirizzi, D.G.,Montemartini, M.,Orrenius, C.,Papeo, G.,Piutti, C.,Salom, B.,Felder, E.R. (登録日: 2013-07-29, 公開日: 2013-10-30, 最終更新日: 2024-11-06)

主引用文献

Casuscelli, F.,Ardini, E.,Avanzi, N.,Casale, E.,Cervi, G.,D'Anello, M.,Donati, D.,Faiardi, D.,Ferguson, R.D.,Fogliatto, G.,Galvani, A.,Marsiglio, A.,Mirizzi, D.G.,Montemartini, M.,Orrenius, C.,Papeo, G.,Piutti, C.,Salom, B.,Felder, E.R.
Discovery and Optimization of Pyrrolo[1,2-A]Pyrazinones Leads to Novel and Selective Inhibitors of Pim Kinases.
Bioorg.Med.Chem., 21:7364-, 2013

PubMed Abstract: A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.

PubMed: 24139169
DOI: 10.1016/J.BMC.2013.09.054

実験手法

X-RAY DIFFRACTION (1.9 Å)