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
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 leu...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-11, Vol.58 (21), p.8373-8386 |
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| creator | Burger, Matthew T Nishiguchi, Gisele Han, Wooseok Lan, Jiong Simmons, Robert Atallah, Gordana Ding, Yu Tamez, Victoriano Zhang, Yanchen Mathur, Michelle Muller, Kristine Bellamacina, Cornelia Lindvall, Mika K Zang, Richard Huh, Kay Feucht, Paul Zavorotinskaya, Tatiana Dai, Yumin Basham, Steve Chan, Julie Ginn, Elaine Aycinena, Alex Holash, Jocelyn Castillo, Joseph Langowski, John L Wang, Yingyun Chen, Min Y Lambert, Amy Fritsch, Christine Kauffmann, Audry Pfister, Estelle Vanasse, K. Gary Garcia, Pablo D |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.5b01275 |
| format | Article |
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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. 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Gary</creatorcontrib><creatorcontrib>Garcia, Pablo D</creatorcontrib><title>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</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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.</description><subject>Amides - chemical synthesis</subject><subject>Amides - chemistry</subject><subject>Amides - therapeutic use</subject><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>Halogenation</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Picolinic Acids - chemical synthesis</subject><subject>Picolinic Acids - chemistry</subject><subject>Picolinic Acids - therapeutic use</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-pim-1 - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UsuO0zAUDQjElIE_QMgLFqkUFz-SJlmOKmAqWqjosI4c52bqwbE7djIiO36BX-RLcB_DkpV17z3n3HPlE0VvKJlRwuh7If3sroNG7qCbZTWhLM-eRhOaMYLTgqTPogkhjGE2Z_wieun9HSGEU8ZfRBdsnpGsKIvJk3fLBkyvWiVFr6xBtkVf_vz6Hac4jum3hG-TbDsNDY6vOmUsznAH_W7UcpTa7uDnqKf70alGGcxxKPAcxyyZ40a1erDO7ndgDu0Mn2slrVZGdKoBFG-W6zTNpwkSaGP7YAQJ06AtaJC9egC0cfZBOaHR0nhwR4Nb1cPB5dpqa2BE68EpA2gFww_olDhqThFNEEuOYhx9Dus8BImdqlVvHVIGLYKHcLJGN04J7VEb2tfQiT6o3h4Ha6HVrRFGKvCvoudtQMHr83sZff_44WZxjVdfPy0XVyssUpr2uOW8SSUtClFzJoC3nBQFFG2d0qytc1pkPBdFU_KSlln4Qj6HnNA8lTyXpWBzfhnFJ929s_cD-L7qlJegtTBgB1_RnPMgX2Y0QNMTVDrrvYO22jvVCTdWlFSHfFQhH9VjPqpzPgLt7XnDUIfZP9JjIAKAnABHuh2cCQf_X_Mv4orKbQ</recordid><startdate>20151112</startdate><enddate>20151112</enddate><creator>Burger, Matthew T</creator><creator>Nishiguchi, Gisele</creator><creator>Han, Wooseok</creator><creator>Lan, Jiong</creator><creator>Simmons, Robert</creator><creator>Atallah, Gordana</creator><creator>Ding, Yu</creator><creator>Tamez, Victoriano</creator><creator>Zhang, Yanchen</creator><creator>Mathur, Michelle</creator><creator>Muller, Kristine</creator><creator>Bellamacina, Cornelia</creator><creator>Lindvall, Mika K</creator><creator>Zang, Richard</creator><creator>Huh, Kay</creator><creator>Feucht, Paul</creator><creator>Zavorotinskaya, Tatiana</creator><creator>Dai, Yumin</creator><creator>Basham, Steve</creator><creator>Chan, Julie</creator><creator>Ginn, Elaine</creator><creator>Aycinena, Alex</creator><creator>Holash, Jocelyn</creator><creator>Castillo, Joseph</creator><creator>Langowski, John L</creator><creator>Wang, Yingyun</creator><creator>Chen, Min Y</creator><creator>Lambert, Amy</creator><creator>Fritsch, Christine</creator><creator>Kauffmann, Audry</creator><creator>Pfister, Estelle</creator><creator>Vanasse, K. Gary</creator><creator>Garcia, Pablo D</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20151112</creationdate><title>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</title><author>Burger, Matthew T ; Nishiguchi, Gisele ; Han, Wooseok ; Lan, Jiong ; Simmons, Robert ; Atallah, Gordana ; Ding, Yu ; Tamez, Victoriano ; Zhang, Yanchen ; Mathur, Michelle ; Muller, Kristine ; Bellamacina, Cornelia ; Lindvall, Mika K ; Zang, Richard ; Huh, Kay ; Feucht, Paul ; Zavorotinskaya, Tatiana ; Dai, Yumin ; Basham, Steve ; Chan, Julie ; Ginn, Elaine ; Aycinena, Alex ; Holash, Jocelyn ; Castillo, Joseph ; Langowski, John L ; Wang, Yingyun ; Chen, Min Y ; Lambert, Amy ; Fritsch, Christine ; Kauffmann, Audry ; Pfister, Estelle ; Vanasse, K. 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Gary</au><au>Garcia, Pablo D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2015-11-12</date><risdate>2015</risdate><volume>58</volume><issue>21</issue><spage>8373</spage><epage>8386</epage><pages>8373-8386</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>26505898</pmid><doi>10.1021/acs.jmedchem.5b01275</doi><tpages>14</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2015-11, Vol.58 (21), p.8373-8386 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1733188951 |
| source | ACS Publications; MEDLINE |
| subjects | Amides - chemical synthesis Amides - chemistry Amides - therapeutic use Animals Cell Line, Tumor Halogenation Humans Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - metabolism Mice Models, Molecular Picolinic Acids - chemical synthesis Picolinic Acids - chemistry Picolinic Acids - therapeutic use Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - therapeutic use Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors Proto-Oncogene Proteins c-pim-1 - metabolism |
| title | 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 |
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