5 research outputs found
MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors
The
Aurora kinases are essential for cell mitosis, and the dysregulation
of Aurora A and B have been linked to the etiology of human cancers.
Investigational agents MLN8054 (<b>8</b>) and alisertib (MLN8237, <b>10</b>) have been identified as high affinity, selective, orally
bioavailable inhibitors of Aurora A that have advanced into human
clinical trials. Alisertib (<b>10</b>) is currently being evaluated
in multiple Phase II and III clinical trials in hematological malignancies
and solid tumors
Treatment-Emergent Mutations in NAEβ Confer Resistance to the NEDD8-Activating Enzyme Inhibitor MLN4924
Discovery of a Potent and Orally Bioavailable Benzolactam-Derived Inhibitor of Polo-Like Kinase 1 (MLN0905)
Discovery of a Potent and Orally Bioavailable Benzolactam-Derived Inhibitor of Polo-Like Kinase 1 (MLN0905)
This article describes the discovery of a series of potent
inhibitors
of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived
chemical series produced an orally bioavailable inhibitor of PLK1
(<b>12c</b>, MLN0905). In vivo pharmacokinetic–pharmacodynamic
experiments demonstrated prolonged mitotic arrest after oral administration
of <b>12c</b> to tumor bearing nude mice. A subsequent efficacy
study in nude mice achieved tumor growth inhibition or regression
in a human colon tumor (HT29) xenograft model