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SEN177 is a novel and highly potent inhibitor of glutaminyl cyclase (QPCT), thereby rescuing the Huntington''s disease (HD)-related phenotypes in cell.
SEN177 is a small molecule inhibitor of glutaminyl cyclase (QC) enzymes, including QPCT and QPCTL. It was originally developed as a QPCT inhibitor for potential treatment of Alzheimer's disease and Huntington's disease. Later studies showed it also inhibits QPCTL, an enzyme that modifies CD47 via pyroglutamate (pGlu) formation, essential for CD47 binding to SIRPα. SEN177 inhibits QPCTL with high efficiency (IC50 0.013 μM) and reduces pGlu-CD47 formation, thereby blocking the CD47-SIRPα interaction and enhancing macrophage- and neutrophil-mediated tumor cell killing. It also rescues mutant huntingtin aggregation and toxicity in cellular and animal models of Huntington's disease. [1][2][3]| Targets |
QPCTL (glutaminyl-peptide cyclotransferase-like protein) – IC50 = 0.013 μM (13 nM). [1]
QPCT (glutaminyl-peptide cyclotransferase) – Ki = 0.020 μM (20 nM); IC50 = 0.05 μM (50 nM). [2] Also inhibits QPCT (hQC2x) with Ki = 20 nM. [2] |
|---|---|
| ln Vitro |
SEN177 (10 μM, 4 days) reduced binding of human SIRPα-Fc to CD47 on A375 melanoma, A431 epidermoid carcinoma, Raji Burkitt's lymphoma, A549 lung cancer, DLD1 colorectal cancer, RKO rectal carcinoma, SKBR3 breast cancer, and HAP1 cells, without affecting total CD47 surface levels as measured by antibodies 2D3 and B6H12. [1]
SEN177 treatment led to near-complete inhibition of pGlu-CD47 formation in A375 cells as shown by isoelectric focusing and SDS-PAGE of anti-CD47 immunoprecipitates. [1] SEN177 (10 μM, 4 days) increased the percentage of phagocytosis of Raji cells by human macrophages in the presence of rituximab, comparable to or greater than CD47 or SIRPα blocking antibodies. [1] SEN177 increased neutrophil-mediated ADCC of A431 cells in the presence of cetuximab. [1] SEN177 (25 μM, 24h) reduced the percentage of HeLa cells with EGFP-HTT(Q74) aggregates in a concentration-dependent manner. [3] SEN177 (25 μM, 24h) reduced the percentage of HEK293 cells with EGFP-A37 aggregates. [3] SEN177 (25 μM) reduced the amount of HTT(1-588)-GFP co-immunoprecipitating with HTT(1-548)-Flag in HeLa cells, indicating reduced mutant huntingtin oligomerisation. [3] SEN177 (50 μM, 24h) reduced the percentage of primary mouse cortical neurons with EGFP-Q80 aggregates. [3] SEN177 (25 μM, 24h) increased alpha B-crystallin (CRYAB) protein levels in HTT(Q74)GFP-expressing cells. [3] SEN177 (50 μM, 24h) reduced the percentage of HeLa cells with apoptotic nuclei induced by EGFP-HTT(Q74). [3] |
| ln Vivo |
In a Drosophila model expressing HTTex1-Q46-eGFP in the eye, SEN177 (50 μM in food) significantly reduced the number of aggregates in fly eyes. [3]
In a Drosophila model expressing HTTEx1-Q120 (GMR-HTT.Q120), SEN177 (50 μM in food) significantly rescued the number of visible rhabdomeres (photoreceptors), preventing neurodegeneration. [3] In a transgenic zebrafish model expressing Htt exon 1 with 71Q fused to EGFP in rod photoreceptors, SEN177 (1 mM, from 3 to 9 days post-fertilization) did not significantly reduce aggregate number or photoreceptor degeneration (unlike SEN817 and SEN180). The poor efficacy was attributed to low bioavailability at tolerated concentrations. [3] |
| Enzyme Assay |
For hQC2x inhibition assay: The activity of hQC2x was measured using a spectrophotometric assay with glutamic dehydrogenase as auxiliary enzyme. Reaction mixture (1 mL) contained 50 mM Tris-HCl pH 8.0, 0.25 mM NADH, 15 mM α-ketoglutaric acid, 30 U glutamic dehydrogenase, 0.1 μM hQC2x, and 1 mM H-Gln-Gln-OH substrate. SEN177 was added and incubated for 2 min at 25°C. The reaction was started by substrate addition and absorbance decrease at 340 nm was monitored. IC50 was determined by nonlinear regression of residual activity vs log inhibitor concentration, giving 0.05 μM. Ki was calculated using IC50 = Ki (1 + S/Km) with Km = 0.65 mM, yielding Ki = 0.020 μM. [2]
For QPCTL inhibition assay: QPCTL protein (7 ng/μL, 12.5 μL) and various concentrations of SEN177 (2.5 μL) were added to a 384-well plate on ice, shaken at 37°C, 100 rpm for 10 min. Then 10 μL of fluorescent substrate H-Gln-AMC (500 μM) was added and incubated for 20 min at 37°C, 100 rpm. Finally, 25 μL of PGPEP I (5.74 ng/μL) was added and incubated for 30 min at 37°C, 100 rpm. Fluorescence was measured at excitation 380 nm/emission 460 nm. IC50 for QPCTL was reported as 0.013 μM. [1] Crystal structure of hQC2x-SEN177 complex was determined at 1.72 Å resolution. SEN177 binds the catalytic Zn(II) ion via the N1 nitrogen of the triazole moiety, displacing the zinc-bound water molecule, and maintains tetrahedral coordination geometry. Additional interactions include a hydrogen bond between triazole N2 and Trp329 Ne1, hydrophobic interactions with Trp207, Phe325, and Trp329, and a hydrogen bond between the fluoro-pyridine fluorine atom and His330 Nδ1. [2] |
| Cell Assay |
Cells (A375, A431, Raji, A549, DLD1, RKO, SKBR3, HAP1) were cultured in appropriate media (DMEM, RPMI, or IMDM) with 10% FCS and antibiotics at 37°C, 5% CO2. For flow cytometry analysis, cells were plated in triplicate in medium containing 0.03% DMSO (vehicle control) or 10 μM SEN177. DMSO or inhibitor was refreshed daily and after 4 days, cells were analyzed for surface binding of anti-CD47 antibodies (CC2C6, 2D3, B6H12) or recombinant SIRPα-Fc by flow cytometry. [1]
For phagocytosis assay: Human monocyte-derived macrophages (differentiated with M-CSF for 7-8 days) were used as effectors. Raji Turquoise-LMNB1 cells were cultured for 5 days with DMSO or 10 μM SEN177. Target cells were labeled with DiIC18 dye, then incubated with rituximab (2 μg/mL) and macrophages (effector/target 1:2) for 3h. Phagocytosis was measured by imaging flow cytometry as percentage of CD11b+ macrophages positive for Turquoise fluorescence. [1] For ADCC assay: A431 cells were labeled with 51Cr (100 μCi, 90 min, 37°C). Neutrophils were isolated and cultured with GM-CSF (10 ng/mL). SEN177 (10 μM) was added 3 days before assay and kept present. Effector/target ratio 50:1, cetuximab present, incubated 4h, 51Cr release measured. [1] For Huntington's disease cell models: HeLa or HEK293 cells were transfected with EGFP-HTT(Q74), EGFP-Q57, EGFP-Q81, or EGFP-A37. After 48h, cells were treated with SEN177 (0-50 μM, 24h). Cells were fixed in 4% PFA, mounted with DAPI, and scored for aggregates and apoptotic nuclei (fragmented/condensed chromatin) under fluorescence microscope. At least 200 transfected cells per slide were scored blind. [3] For primary cortical neurons: Neurons from E16.5 mouse embryos were cultured for 5 days, then infected with lentivirus expressing EGFP-Q80 and treated with SEN177 (50 μM, 24h). Cells were fixed and aggregates counted. [3] For co-immunoprecipitation: HeLa cells expressing HTT(1-588)-Flag(Q138) and HTT(1-548)-GFP(Q138) were treated with SEN177 (25 μM, 24h). Lysates were immunoprecipitated with anti-Flag or anti-GFP antibodies, and co-precipitated protein detected by western blot. [3] |
| Animal Protocol |
For Drosophila experiments: Flies were reared on food containing SEN177 (50 μM) dissolved in DMSO or DMSO alone. The progeny were transferred every 2 days to fresh food containing the inhibitor or DMSO. For aggregate counting: virgins of genotype w; GMR-GAL4; UAS-Httex1-Q46-eGFP were crossed with w1118 males, and female progeny scored 15 days post-eclosion. For pseudopupil assay: virgins of genotype w; {GMR-HD.Q120}2.4 (GMR-HTT.Q120) were mated with w1118 control males for 48h on standard food, then transferred to food containing 50 μM SEN177. Flies were scored 3-4 days post-eclosion. Approximately 10 individuals per genotype, scoring 15 ommatidia per eye. [3]
For zebrafish experiments: Transgenic HD zebrafish larvae (Tg:rho-EGFP-HTT71Q) were used. From 3 to 9 days post-fertilization, larvae were dark-reared in embryo medium containing 1 mM SEN177 (or DMSO control). Medium and compounds were replenished daily. At 7 d.p.f., larvae were fixed in 4% PFA, cryosectioned (10 μm), and aggregates counted over 100 μm of central retina (n=5 fish, 10 eyes). At 9 d.p.f., sections were stained with anti-rhodopsin antibody to assess photoreceptor area. [3] |
| ADME/Pharmacokinetics |
SEN177 has poor pharmacokinetics in mice, with a drop in serum concentration of approximately 1,000-fold in an 8-hour time period. This precluded in vivo experiments using this inhibitor in mouse models. [1]
In vitro ADME properties: solubility measurements, CNS membrane permeability assay (PAMPA-BBB), and stability in presence of human CYP3A4 were assessed during compound development (detailed values not provided in the text). [3] |
| Toxicity/Toxicokinetics |
Maximum tolerated concentration in larval zebrafish was determined for SEN177 (along with SEN817 and SEN180) using wild-type larvae from 2 to 3 days post-fertilization over log intervals from 100 nM to 1 mM. The maximum non-toxic concentration (MTC) for SEN177 was 1 mM. Higher concentrations were toxic. [3]
In Drosophila, SEN177 at 50 μM in food was well tolerated with no apparent toxicity. [3] In mammalian cell lines (HeLa, HEK293, primary neurons), SEN177 was used at concentrations up to 50 μM without overt cytotoxicity as assessed by nuclear morphology and caspase activity. [3] |
| References |
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| Additional Infomation |
SEN177 belongs to the bipyridine class of compounds. SEN177 was identified as a QPCT inhibitor through structure-based drug design using ensemble docking models based on X-ray structures (PDB: 2AFW, 2AFX, 2AFZ, 3PBB, 3SIO) and molecular dynamics simulations. It contains a triazole ring that coordinates the catalytic zinc ion. [2][3]
SEN177 also inhibits QPCTL with high efficiency (IC50 0.013 μM) and reduces CD47 pyroglutamation, thereby blocking CD47-SIRPα interaction and enhancing antibody-dependent cellular phagocytosis and cytotoxicity. [1] In Huntington's disease models, SEN177 reduces mutant huntingtin aggregation and toxicity via induction of alpha B-crystallin (CRYAB), a small heat shock protein that acts as a molecular chaperone. [3] Poor pharmacokinetics in mice (rapid clearance, ~1000-fold drop in serum over 8h) limits its use in mouse efficacy studies. [1] |
| Molecular Formula |
C18H19FN6
|
|---|---|
| Molecular Weight |
338.382066011429
|
| Exact Mass |
338.165
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| Elemental Analysis |
C, 63.89; H, 5.66; F, 5.61; N, 24.84
|
| CAS # |
2117405-13-5
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| Related CAS # |
2117405-13-5;
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| PubChem CID |
91618245
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| Appearance |
Brown to gray solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
581.3±60.0 °C at 760 mmHg
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| Flash Point |
305.3±32.9 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.683
|
| LogP |
1.12
|
| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
25
|
| Complexity |
430
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
FC1=CC=C(C=N1)C1=CC=CN=C1N1CCC(C2=NN=CN2C)CC1
|
| InChi Key |
AJIAMIPUWJQSPR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H19FN6/c1-24-12-22-23-17(24)13-6-9-25(10-7-13)18-15(3-2-8-20-18)14-4-5-16(19)21-11-14/h2-5,8,11-13H,6-7,9-10H2,1H3
|
| Chemical Name |
2-fluoro-5-[2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridin-3-yl]pyridine
|
| Synonyms |
SEN-177; SEN 177;2117405-13-5; SEN177; 3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine; 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)pyridine; RefChem:493903;
|
| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~33.3 mg/mL (~98.5 mM)
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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