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 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.
Matthew T
MT
Burger
Gisele
G
Nishiguchi
Wooseok
W
Han
Jiong
J
Lan
Robert
R
Simmons
Gordana
G
Atallah
Yu
Y
Ding
Victoriano
V
Tamez
Yanchen
Y
Zhang
Michelle
M
Mathur
Kristine
K
Muller
Cornelia
C
Bellamacina
Mika K
MK
Lindvall
Richard
R
Zang
Kay
K
Huh
Paul
P
Feucht
Tatiana
T
Zavorotinskaya
Yumin
Y
Dai
Steve
S
Basham
Julie
J
Chan
Elaine
E
Ginn
Alex
A
Aycinena
Jocelyn
J
Holash
Joseph
J
Castillo
John L
JL
Langowski
Yingyun
Y
Wang
Min Y
MY
Chen
Amy
A
Lambert
Oncology Research, Novartis Institutes for Biomedical Research , CH-4056, Basel, Switzerland.
Christine
C
Fritsch
Oncology Research, Novartis Institutes for Biomedical Research , CH-4056, Basel, Switzerland.
Audry
A
Kauffmann
Oncology Research, Novartis Institutes for Biomedical Research , CH-4056, Basel, Switzerland.
Estelle
E
Pfister
Translational Clinical Oncology, Novartis Institutes for Biomedical Research , 220 Massachusetts Avenue, Cambridge Massachusetts 02139, United States.
K Gary
KG
Vanasse
Pablo D
PD
Garcia
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D054879:Halogenation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D010848:Picolinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D010848:Picolinic Acids; C094167:Pim2 protein, mouse; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C496636:Pim1 protein, mouse; C488192:Pim3 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; C003142:picolinamide