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

Summary for 5DWR

• Entry DOI: 10.2210/pdb5dwr/pdb
• Related: 4N70
• Descriptor: 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)
• Functional Keywords: pim1, moloney murine leukemia, pim447, kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• Total number of polymer chains: 1
• Total formula weight: 38037.16

Authors

Bellamacina, C.,Bussiere, D.,Burger, M. (deposition date: 2015-09-22, release date: 2015-11-11, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)