3 research outputs found
Optimization of Benzodiazepinones as Selective Inhibitors of the X‑Linked Inhibitor of Apoptosis Protein (XIAP) Second Baculovirus IAP Repeat (BIR2) Domain
The
IAPs are key regulators of the apoptotic pathways and are commonly
overexpressed in many cancer cells. IAPs contain one to three BIR
domains that are crucial for their inhibitory function. The pro-survival
properties of XIAP come from binding of the BIR domains to the pro-apoptotic
caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while
the BIR2 domain binds and inhibits the terminal caspases 3 and 7.
While XIAP BIR3 inhibitors have previously been reported, they also
inhibit cIAP1/2 and promote the release of TNFα, potentially
limiting their therapeutic utility. This paper will focus on the optimization
of selective XIAP BIR2 inhibitors leading to the discovery of highly
potent benzodiazepinone <b>36</b> (IC<sub>50</sub> = 45 nM),
which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3
and shows efficacy in a xenograft pharmacodynamic model monitoring
caspase activity while not promoting the release of TNFα in
vitro
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
Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors
Structure–activity relationships
in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides
identified highly potent inhibitors of Îł-secretase mediated
signaling of Notch1/2/3/4 receptors. On the basis of its robust in
vivo efficacy at tolerated doses in Notch driven leukemia and solid
tumor xenograft models, <b>12</b> (BMS-906024) was selected
as a candidate for clinical evaluation