3 research outputs found
Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors
Proviral insertion of Moloney virus
(PIM) 1, 2, and 3 kinases are
serine/threonine kinases that normally function in survival and proliferation
of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently
observed in many human malignancies, including multiple myeloma, non-Hodgkins
lymphoma, and myeloid leukemias, there is interest in determining
whether selective PIM inhibition can improve outcomes of these human
cancers. Herein, we describe our efforts toward this goal. The structure
guided optimization of a singleton high throughput screening hit in
which the potency against all three PIM isoforms was increased >10,000-fold
to yield compounds with pan PIM <i>K</i><sub>i</sub>s <
10 pM, nanomolar cellular potency, and in vivo activity in an acute
myeloid leukemia Pim-dependent tumor model is described
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
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
Design and Discovery of <i>N</i>‑(2-Methyl-5′-morpholino-6′-((tetrahydro‑2<i>H</i>‑pyran-4-yl)oxy)-[3,3′-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers
RAS oncogenes have been implicated
in >30% of human cancers, all
representing high unmet medical need. The exquisite dependency on
CRAF kinase in KRAS mutant tumors has been established in genetically
engineered mouse models and human tumor cells. To date, many small
molecule approaches are under investigation to target CRAF, yet kinase-selective
and cellular potent inhibitors remain challenging to identify. Herein,
we describe <b>14</b> (RAF709) [Aversa, Biaryl amide
compounds as kinase inhibitors and their preparation. WO 2014151616, 2014], a selective B/C RAF inhibitor, which
was developed through a hypothesis-driven approach focusing on drug-like
properties. A key challenge encountered in the medicinal chemistry
campaign was maintaining a balance between good solubility and potent
cellular activity (suppression of pMEK and proliferation) in KRAS
mutant tumor cell lines. We investigated the small molecule crystal
structure of lead molecule <b>7</b> and hypothesized that disruption
of the crystal packing would improve solubility, which led to a change
from <i>N</i>-methylpyridone to a tetrahydropyranyl oxy-pyridine
derivative. <b>14</b> proved to be soluble, kinase selective,
and efficacious in a KRAS mutant xenograft model