SEN177
目录号 : GC68363SEN177 是一种有效的谷氨酰胺环化酶 (QPCT) 抑制剂，对谷氨酰胺肽环转移酶 (QPCTL) 的 IC50 为 0.013 μM。SEN177 对人谷氨酰胺环化酶 (hQC) 的 Ki 为 20 nM。SEN177 大大降低了突变 HTT 寡聚化的早期阶段，并降低了具有 Q80 聚集体的神经元的百分比。SEN177 具有研究亨廷顿病的潜力。
Cas No.:2117405-13-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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SEN177 is a potent glutaminyl cyclase (QPCT) inhibitor with an IC50 of 0.013μM for glutaminyl-peptide cyclotransferase-like (QPCTL). SEN177 has a Ki of 20 nM for human glutaminyl cyclase (hQC). SEN177 greatly reduces the early stages of mutant HTT oligomerisation and reduces the percentage of neurons with Q80 aggregates. SEN177 has the potential for Huntington's disease research[1].
[1]. Meike E W Logtenberg, et al. Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy. Nat Med
[2]. Cecilia Pozzi, et al. The structure of the human glutaminyl cyclase-SEN177 complex indicates routes for developing new potent inhibitors as possible agents for the treatment of neurological disorders. J Biol Inorg Chem. 2018 Dec;23(8):1219-1226.
[3]. Maria Jimenez-Sanchez, et al. siRNA screen identifies QPCT as a druggable target for Huntington's disease. Nat Chem Biol. 2015 May;11(5):347-354.
| Cas No. | 2117405-13-5 | SDF | Download SDF |
| 分子式 | C18H19FN6 | 分子量 | 338.38 |
| 溶解度 | DMSO : 33.33 mg/mL (98.50 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.9553 mL | 14.7763 mL | 29.5526 mL |
| 5 mM | 0.5911 mL | 2.9553 mL | 5.9105 mL |
| 10 mM | 0.2955 mL | 1.4776 mL | 2.9553 mL |
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2.
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The structure of the human glutaminyl cyclase-SEN177 complex indicates routes for developing new potent inhibitors as possible agents for the treatment of neurological disorders
J Biol Inorg Chem 2018 Dec;23(8):1219-1226.PMID:30132075DOI:10.1007/s00775-018-1605-1.
Recent evidence links the role of human glutaminyl cyclase (hQC) to the amyloidogenic process involved in Alzheimer's disease (AD). hQC is a zinc enzyme present in neuronal tissue and its activity is responsible for the cyclization of N-terminal Gln or Glu β-amyloid peptides, leading to N-pyroglutamic acid peptides (pE-Aβ) that is probably a crucial event in the initiation and progress of the disease. Indeed, pE-containing peptides exhibit an elevated neurotoxicity and a tendency to aggregate. These observations render hQC inhibition an attractive strategy for developing new molecules active against AD. We present here the crystal structure of hQC in complex with SEN177, a newly designed molecule. The SEN177-binding mode to hQC differs from that of the known hQC inhibitors. SEN177 Ki on hQC is 20 nM, comparable or better than that of the most potent known hQC inhibitors PBD150 and PQ912. In addition, SEN177 already demonstrated relevant pharmacological properties in in vivo models of Huntington's disease. All these properties make SEN177 an important scaffold for developing molecules acting on AD and related diseases.
A homogeneous SIRPα-CD47 cell-based, ligand-binding assay: Utility for small molecule drug development in immuno-oncology
PLoS One 2020 Apr 2;15(4):e0226661.PMID:32240171DOI:10.1371/journal.pone.0226661.
CD47 is an immune checkpoint protein that downregulates both the innate and adaptive anti-tumor immune response via its counter receptor SIRPα. Biologics, including humanized CD47 monoclonal antibodies and decoy SIRPα receptors, that block the SIRPα-CD47 interaction, are currently being developed as cancer immunotherapy agents. However, adverse side effects and limited penetration of tumor tissue associated with their structure and large size may impede their clinical application. We recently developed a quantitative high throughput screening assay platform to identify small molecules that disrupt the binding of SIRPα and CD47 as an alternative approach to these protein-based therapeutics. Here, we report on the development and optimization of a cell-based binding assay to validate active small molecules from our biochemical screening effort. This assay has a low volume, high capacity homogenous format that relies on laser scanning cytometry (LSC) and associated techniques to enhance signal to noise measurement of cell surface binding. The LSC assay is specific, concentration dependent, and validated for the two major human SIRPα variants (V1 and V2), with results that parallel those of our biochemical data as well as published studies. We also utilized the LSC assay to confirm published studies showing that the inhibition of amino-terminal pyroglutamate formation on CD47 using the glutaminyl cyclase inhibitor SEN177 disrupts SIRPα binding. The SIRPα-CD47 interaction could be quantitatively measured in live and fixed tumor cells. Use of fixed cells reduces the burden of cell maintenance and provides stable cell standards to control for inter- and intra-assay variations. We also demonstrate the utility of the assay to characterize the activity of the first reported small molecule antagonists of the SIRPα-CD47 interaction. This assay will support the screening of thousands of compounds to identify or validate active small molecules as hits, develop structure activity relationships and assist in the optimization of hits to leads by a typical iterative medicinal chemistry campaign.
Enhancement of epidermal growth factor receptor antibody tumor immunotherapy by glutaminyl cyclase inhibition to interfere with CD47/signal regulatory protein alpha interactions
Cancer Sci 2021 Aug;112(8):3029-3040.PMID:34058788DOI:10.1111/cas.14999.
Integrin associated protein (CD47) is an important target in immunotherapy, as it is expressed as a "don't eat me" signal on many tumor cells. Interference with its counter molecule signal regulatory protein alpha (SIRPα), expressed on myeloid cells, can be achieved with blocking Abs, but also by inhibiting the enzyme glutaminyl cyclase (QC) with small molecules. Glutaminyl cyclase inhibition reduces N-terminal pyro-glutamate formation of CD47 at the SIRPα binding site. Here, we investigated the impact of QC inhibition on myeloid effector cell-mediated tumor cell killing by epidermal growth factor receptor (EGFR) Abs and the influence of Ab isotypes. SEN177 is a QC inhibitor and did not interfere with EGFR Ab-mediated direct growth inhibition, complement-dependent cytotoxicity, or Ab-dependent cell-mediated cytotoxicity (ADCC) by mononuclear cells. However, binding of a human soluble SIRPα-Fc fusion protein to SEN177 treated cancer cells was significantly reduced in a dose-dependent manner, suggesting that pyro-glutamate formation of CD47 was affected. Glutaminyl cyclase inhibition in tumor cells translated into enhanced Ab-dependent cellular phagocytosis by macrophages and enhanced ADCC by polymorphonuclear neutrophilic granulocytes. Polymorphonuclear neutrophilic granulocyte-mediated ADCC was significantly more effective with EGFR Abs of human IgG2 or IgA2 isotypes than with IgG1 Abs, proposing that the selection of Ab isotypes could critically affect the efficacy of Ab therapy in the presence of QC inhibition. Importantly, QC inhibition also enhanced the therapeutic efficacy of EGFR Abs in vivo. Together, these results suggest a novel approach to specifically enhance myeloid effector cell-mediated efficacy of EGFR Abs by orally applicable small molecule QC inhibitors.