5 research outputs found
Supplemental_Info_for_HTFC-MLR-Assay_by_Fan_et_al – Supplemental material for Miniaturized High-Throughput Multiparameter Flow Cytometry Assays Measuring In Vitro Human Dendritic Cell Maturation and T-Cell Activation in Mixed Lymphocyte Reactions
<p>Supplemental material, Supplemental_Info_for_HTFC-MLR-Assay_by_Fan_et_al for Miniaturized High-Throughput Multiparameter Flow Cytometry Assays Measuring In Vitro Human Dendritic Cell Maturation and T-Cell Activation in Mixed Lymphocyte Reactions by Yi Fan, Joseph G. Naglich, Jennifer D. Koenitzer, Humberto Ribeiro, Jonathan Lippy, Jordan Blum, Xin Li, Christina Milburn, Bryan Barnhart, Litao Zhang and Mark P. Fereshteh in SLAS Discovery</p
Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase‑3 Inhibitors
GSK-3
is a serine/threonine kinase that has numerous substrates.
Many of these proteins are involved in the regulation of diverse cellular
functions, including metabolism, differentiation, proliferation, and
apoptosis. Inhibition of GSK-3 may be useful in treating a number
of diseases including Alzheimer’s disease (AD), type II diabetes,
mood disorders, and some cancers, but the approach poses significant
challenges. Here, we present a class of isonicotinamides that are
potent, highly kinase-selective GSK-3 inhibitors, the members of which
demonstrated oral activity in a triple-transgenic mouse model of AD.
The remarkably high kinase selectivity and straightforward synthesis
of these compounds bode well for their further exploration as tool
compounds and therapeutics
Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase‑3 Inhibitors
GSK-3
is a serine/threonine kinase that has numerous substrates.
Many of these proteins are involved in the regulation of diverse cellular
functions, including metabolism, differentiation, proliferation, and
apoptosis. Inhibition of GSK-3 may be useful in treating a number
of diseases including Alzheimer’s disease (AD), type II diabetes,
mood disorders, and some cancers, but the approach poses significant
challenges. Here, we present a class of isonicotinamides that are
potent, highly kinase-selective GSK-3 inhibitors, the members of which
demonstrated oral activity in a triple-transgenic mouse model of AD.
The remarkably high kinase selectivity and straightforward synthesis
of these compounds bode well for their further exploration as tool
compounds and therapeutics
Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms
JAK2 kinase inhibitors are a promising
new class of agents for
the treatment of myeloproliferative neoplasms and have potential for
the treatment of other diseases possessing a deregulated JAK2-STAT
pathway. X-ray structure and ADME guided refinement of C-4 heterocycles
to address metabolic liability present in dialkylthiazole <b>1</b> led to the discovery of a clinical candidate, BMS-911543 (<b>11</b>), with excellent kinome selectivity, <i>in vivo</i> PD activity, and safety profile
Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3‑Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders
PI3Kδ plays an important role
controlling immune cell function and has therefore been identified
as a potential target for the treatment of immunological disorders.
This article highlights our work toward the identification of a potent,
selective, and efficacious PI3Kδ inhibitor. Through careful
SAR, the successful replacement of a polar pyrazole group by a simple
chloro or trifluoromethyl group led to improved Caco-2 permeability,
reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity
profile while maintaining potency in the CD69 hWB assay. The optimization
of the aryl substitution then identified a 4′-CN group that
improved the human/rodent correlation in microsomal metabolic stability.
Our lead molecule is very potent in PK/PD assays and highly efficacious
in a mouse collagen-induced arthritis model