Anti-NME2 monoclonal antibody, clone 2G3

Reaction of N-R,N'-R'-2,5-diiminopyrroles (R = R' = S-CH(Me)Ph; R = R' = CH2Ph; R = S-CH(Me)Ph, R' = H) with Cu(OMe)(2) in the presence of chelating alcohols, ROH (R1 = C(2)H(4)NMe2, R2 = C2H4Py, R3 = CH2Py, R4 = CMe2Py) yielded the dinuclear, alkoxide-bridged complexes L2Cu2(OR)(2). The complexes catalyze the polymerization of rac-lactide at room temperature with catalyst concentrations of 1-3 mM in 4-24 h (v = k[cat] [monomer] with k = [2.3(5)] x 10(2)- [6.5(6)] X 10(3) M-1 h(-1)). EPR and mechanistic studies indicate that the complexes remain dinuclear during the polymerization reaction. In complexes with OR1, both alkoxides of the dimer initiate polymerization, with OR2 or OR3 only one alkoxide initiates polymerization, and OR4 is inactive in polymerization. The nature of the bridging ligand in the dinuclear complex determines stereocontrol. Independent of the spectator ligand L, complexes which retain an OR3 or OR4 bridging ligand in the active species show preference for isotactic polymerizations (P-m = 0.60-0.75), while those with only polymeryloxo bridges or OR2 as the bridging ligand provide atactic polymer. Stereocontrol follows a chain-end control mechanism, with the catalytic site likely adapting to the configuration of the chain end.

Transcriptional activation of the human telomerase reverse transcriptase (hTERT) gene, which remains repressed in adult somatic cells, is critical during tumorigenesis. Several transcription factors and the epigenetic state of the hTERT promoter are known to be important for tight control of hTERT in normal tissues, but the molecular mechanisms leading to hTERT reactivation in cancer are not well-understood. Surprisingly, here we found occupancy of the metastasis suppressor non-metastatic 2 (NME2) within the hTERT core promoter in HT1080 fibrosarcoma cells and HCT116 colon cancer cells and NME2-mediated transcriptional repression of hTERT in these cells. We also report that loss of NME2 results in up-regulated hTERT expression. Mechanistically, additional results indicated that the RE1-silencing transcription factor (REST)-lysine-specific histone demethylase 1 (LSD1) co-repressor complex associates with the hTERT promoter in an NME2-dependent way and that this assembly is required for maintaining repressive chromatin at the hTERT promoter. Interestingly, a G-quadruplex motif at the hTERT promoter was essential for occupancy of NME2 and the REST repressor complex on the hTERT promoter. In light of this mechanistic insight, we studied the effects of G-quadruplex-binding ligands on hTERT expression and observed that several of these ligands repressed hTERT expression. Together, our results support a mechanism of hTERT epigenetic control involving a G-quadruplex promoter motif, which potentially can be targeted by tailored small molecules.