4 research outputs found
Importance of extra- and intracellular domains of TLR1 and TLR2 in NFkappa B signaling
Recognition of ligands by toll-like receptor (TLR) 2 requires interactions with other TLRs. TLRs form a combinatorial repertoire to discriminate between the diverse microbial ligands. Diversity results from extracellular and intracellular interactions of different TLRs. This paper demonstrates that TLR1 and TLR2 are required for ara-lipoarabinomannan- and tripalmitoyl cysteinyl lipopeptide-stimulated cytokine secretion from mononuclear cells. Confocal microscopy revealed that TLR1 and TLR2 cotranslationally form heterodimeric complexes on the cell surface and in the cytosol. Simultaneous cross-linking of both receptors resulted in ligand-independent signal transduction. Using chimeric TLRs, we found that expression of the extracellular domains along with simultaneous expression of the intracellular domains of both TLRs was necessary to achieve functional signaling. The domains from each receptor did not need to be contained within a single contiguous protein. Chimeric TLR analysis further defined the toll/IL-1R domains as the area of crucial intracellular TLR1-TLR2 interaction
Discovery of a Novel Class of Dimeric Smac Mimetics as Potent IAP Antagonists Resulting in a Clinical Candidate for the Treatment of Cancer (AZD5582)
A series of dimeric compounds based
on the AVPI motif of Smac were
designed and prepared as antagonists of the inhibitor of apoptosis
proteins (IAPs). Optimization of cellular potency, physical properties,
and pharmacokinetic parameters led to the identification of compound <b>14</b> (AZD5582), which binds potently to the BIR3 domains of
cIAP1, cIAP2, and XIAP (IC<sub>50</sub> = 15, 21, and 15 nM, respectively).
This compound causes cIAP1 degradation and induces apoptosis in the
MDA-MB-231 breast cancer cell line at subnanomolar concentrations
in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing
mice, <b>14</b> results in cIAP1 degradation and caspase-3 cleavage
within tumor cells and causes substantial tumor regressions following
two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed
with <b>14</b> in only a small subset of the over 200 cancer
cell lines examined, consistent with other published IAP inhibitors.
As a result of its in vitro and in vivo profile, <b>14</b> was
nominated as a candidate for clinical development