5DWR

Identification of N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1,2 and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies

5DWR の概要

• エントリーDOI: 10.2210/pdb5dwr/pdb
• 関連するPDBエントリー: 4N70
• 分子名称: Serine/threonine-protein kinase pim-1, N-{4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide (3 entities in total)
• 機能のキーワード: pim1, moloney murine leukemia, pim447, kinase inhibitor, 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: 38037.16

構造登録者

Bellamacina, C.,Bussiere, D.,Burger, M. (登録日: 2015-09-22, 公開日: 2015-11-11, 最終更新日: 2024-10-16)

主引用文献

Burger, M.T.,Nishiguchi, G.,Han, W.,Lan, J.,Simmons, R.,Atallah, G.,Ding, Y.,Tamez, V.,Zhang, Y.,Mathur, M.,Muller, K.,Bellamacina, C.,Lindvall, M.K.,Zang, R.,Huh, K.,Feucht, P.,Zavorotinskaya, T.,Dai, Y.,Basham, S.,Chan, J.,Ginn, E.,Aycinena, A.,Holash, J.,Castillo, J.,Langowski, J.L.,Wang, Y.,Chen, M.Y.,Lambert, A.,Fritsch, C.,Kauffmann, A.,Pfister, E.,Vanasse, K.G.,Garcia, P.D.
Identification of N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies.
J.Med.Chem., 58:8373-8386, 2015

PubMed Abstract: Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound 3, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies.

PubMed: 26505898
DOI: 10.1021/acs.jmedchem.5b01275

実験手法

X-RAY DIFFRACTION (2 Å)