Therapeutic potential of glutaminyl cyclases: Current status and emerging trends

Isoglutaminyl Cyclase Overexpression Enhances KYSE30 Cancer Cell Proliferation and Migration via the MAPK Signaling Pathway

“…In previous reports, pE modification of substrates catalyzed by the upregulated isoQC in the progression of cancer and inflammation were mainly investigated. 27,28 Interestingly, the effects of iso-QC overexpression on the proliferation invasion and metastasis of KYSE30 cells were confirmed here based on the cell viability assay kit, transwell, wound-healing, and colony formation assays. So, targeting upregulated isoQC should be considered as another strategy to suppress proliferation, migration, and invasion of cancer cells.…”

“…Various studies have shown that upregulated isoQC contributes to the initiation of disorders such as inflammation and cancer by catalyzing the generation of pE modified substrates. − However, the pathological mechanisms by which upregulated isoQC acts is unclear. Here, we aimed to understand how upregulated isoQC involves the initiation of diseases.…”

Identification of BACE-1 inhibitors through directed C(sp3)–H activation on 5-oxo-pyrrolidine-3-carboxylic acid derivatives

“…19,20 In particular, fully substituted 5-oxopyrrolidines bearing a carbonyl moiety in position 3 are found in many bioactive molecules and natural products involved in the treatment of CNS diseases. Just to give some examples, different Endothelin Receptor Antagonists 21 and Glutaminyl-Peptide CycloTransferase-Like (QPCTL) inhibitors, 22 used for the treatment of Alzheimer's Disease, contain a fully substituted 5-oxopyrrolidines. Also, this scaffold is present in heliotropamide A and bisavenanthramide B-6 natural products used in traditional Chinese medicine, 23 for their acetylcholinesterase inhibitory activity and their neuroprotective effects (Fig.…”

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson’s Disease Mouse Model

“…The sQC N-terminus contains a signal peptide responsible for secretion, while the gQC Nterminus bears a peptide to anchor Golgi apparatus. 19,20,26 In addition, sQC and gQC have different flexible active site loops, contributing to capture and recognize different protein substrates. 29 To date, a number of inhibitors targeting sQC and gQC have been reported (Figure 1b).…”

“…By contrast, 18 with a benzylamine exhibited apparently reduced inhibitory activity of either sQC or gQC. Replacement of benzylamine with 4-hydroxycyclohexane-1-carboxamide (19) had improved inhibitory activity and LE, especially for sQC, with an IC 50 value of 0.85 μM. In general, introducing suitable substituents at the R 1 position (e.g., 15, 17, and 19) proves advantageous in enhancing the inhibitory activity against sQC and gQC; conversely, even minor substituents at the R 2 position tend to hinder the inhibition of sQC and gQC.…”