2. Academic Validation
  3. 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

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. 2015 Nov 12;58(21):8373-86. doi: 10.1021/acs.jmedchem.5b01275.
Matthew T Burger,  Gisele Nishiguchi,  Wooseok Han,  Jiong Lan,  Robert Simmons,  Gordana Atallah,  Yu Ding,  Victoriano Tamez,  Yanchen Zhang,  Michelle Mathur,  Kristine Muller,  Cornelia Bellamacina,  Mika K Lindvall,  Richard Zang,  Kay Huh,  Paul Feucht,  Tatiana Zavorotinskaya,  Yumin Dai,  Steve Basham,  Julie Chan,  Elaine Ginn,  Alex Aycinena,  Jocelyn Holash,  Joseph Castillo,  John L Langowski,  Yingyun Wang,  Min Y Chen,  Amy Lambert,  Christine Fritsch 1,  Audry Kauffmann 1,  Estelle Pfister 1,  K Gary Vanasse 2,  Pablo D Garcia
Affiliations

Affiliations

  • 1 Oncology Research, Novartis Institutes for Biomedical Research , CH-4056, Basel, Switzerland.
  • 2 Translational Clinical Oncology, Novartis Institutes for Biomedical Research , 220 Massachusetts Avenue, Cambridge Massachusetts 02139, United States.
PMID: 26505898 DOI: 10.1021/acs.jmedchem.5b01275
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.

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