5 research outputs found
Discovery of a Selective and Potent Inhibitor of Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2 (MNK1/2) Utilizing Structure-Based Drug Design
The discovery of a highly potent
and selective small molecule inhibitor <b>9</b> for in vitro
target validation of MNK1/2 kinases is described.
The aminopyrazine benzimidazole series was derived from an HTS hit
and optimized by utilization of a docking model, conformation analysis,
and binding pocket comparison against antitargets
Discovery of a Selective and Potent Inhibitor of Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2 (MNK1/2) Utilizing Structure-Based Drug Design
The discovery of a highly potent
and selective small molecule inhibitor <b>9</b> for in vitro
target validation of MNK1/2 kinases is described.
The aminopyrazine benzimidazole series was derived from an HTS hit
and optimized by utilization of a docking model, conformation analysis,
and binding pocket comparison against antitargets
Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma
Abrogation of errant signaling along
the MAPK pathway through the
inhibition of B-RAF kinase is a validated approach for the treatment
of pathway-dependent cancers. We report the development of imidazo-benzimidazoles
as potent B-RAF inhibitors. Robust <i>in vivo</i> efficacy
coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and
PD-efficacy relationships led to the identification of RAF265, <b>1</b>, which has advanced into clinical trials
Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor
The
discovery of inhibitors targeting novel allosteric kinase sites is
very challenging. Such compounds, however, once identified could offer
exquisite levels of selectivity across the kinome. Herein we report
our structure-based optimization strategy of a dibenzodiazepine hit <b>1</b>, discovered in a fragment-based screen, yielding highly
potent and selective inhibitors of PAK1 such as <b>2</b> and <b>3</b>. Compound <b>2</b> was cocrystallized with PAK1 to
confirm binding to an allosteric site and to reveal novel key interactions.
Compound <b>3</b> modulated PAK1 at the cellular level and due
to its selectivity enabled valuable research to interrogate biological
functions of the PAK1 kinase
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