Identification
of <i>N</i>‑(4-((1<i>R</i>,3<i>S</i>,5<i>S</i>)‑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
- Publication date
- Publisher
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 <b>8</b> (PIM447) are described. Starting
from the reported aminopiperidyl pan PIM kinase inhibitor compound <b>3</b>, 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 <b>8</b> entered the clinic in 2012 in multiple
myeloma patients and is currently in several phase 1 trials of cancer
patients with hematological malignancies