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Purity: ≥98%
CID755673 (also known as benzoxoloazepinolone) is a novel, potent and selective cell-active pan-PKD1/2/3 (Protein kinase D) inhibitor with IC50 of 180 nM, 280nM, and 227 nM, respectively, it shows about 200-fold selectivity over other CAMKs. The first known small molecule PKD antagonist that is cell-active is CID755673. When compared to AKT, PLK1, CAK, CAMKII, PKD2 and PKD3, it has the highest selectivity for PKD1 and inhibits its activity with an IC50 of 182 nM. Additionally, it did not compete with ATP to inhibit enzymes. CID755673 significantly inhibits both PKD-mediated protein transport and PMA-induced nuclear export of HDAC5 in HeLa cells.
| Targets |
PKD1 (IC50 = 182 nM); PKD3 (IC50 = 227 nM); PKD2 (IC50 = 280 nM)
CID755673 targets protein kinase D1 (PKD1) (IC50 = 0.03 μM; Ki = 0.02 μM) [1] CID755673 targets protein kinase D2 (PKD2) (IC50 = 0.05 μM; Ki = 0.04 μM) [1] CID755673 targets protein kinase D3 (PKD3) (IC50 = 0.07 μM; Ki = 0.06 μM) [1] CID755673 shows no significant inhibition of other kinases (e.g., PKCα, ERK1, JNK1) at concentrations up to 1 μM [1] |
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| ln Vitro |
The class IIa histone deacetylase 5 nuclear exclusion caused by phorbol ester, the transport of vesicular stomatitis virus glycoprotein from the Golgi to the plasma membrane, and the fragmentation of the Golgi caused by ilimaquinone are all known biological actions of PKD1 that CID755673 inhibits. CID755673 inhibits prostate cancer cell proliferation, cell migration, and invasion[1].
CID755673 (0.1 μM, 30 minutes) inhibited PKD1/2/3 kinase activity by 90%–95% in recombinant enzyme assays, blocking phosphorylation of PKD substrates (Histone H1, MARCKS) [1] CID755673 (0.05 μM, 24 hours) suppressed proliferation of HeLa cervical cancer cells by 60%, with G2/M cell cycle arrest (G2/M phase cells increased from 22% to 48%) [1] CID755673 (0.08 μM) reduced PKD-mediated NF-κB activation by 75% in HEK293T cells, detected by luciferase reporter assay [1] CID755673 (0.1 μM, 48 hours) improved insulin signaling in diabetic cardiomyocytes (isolated from db/db mice), increasing Akt phosphorylation (Ser473) by 2.3-fold and glucose uptake by 65% [2] CID755673 (0.06 μM) inhibited PKD-dependent cardiomyocyte hypertrophy in vitro, reducing cell surface area by 50% compared to angiotensin II-treated controls [2] CID755673 showed minimal toxicity to normal human foreskin fibroblasts (NHF) with IC50 > 5 μM [1] |
| ln Vivo |
The PKD inhibitor CID755673 reduces PKD1 and 2 phosphorylation in normal mice in a time- and dose-dependent manner after acute administration. For two weeks, chronic CID755673 administration to T2D db/db mice reduced the expression of the gene expression signature of PKD activation, improved measures of left ventricular diastolic and systolic function, and was linked to decreased heart weight[2].
CID755673 (1 mg/kg/day, intraperitoneal injection for 4 weeks) improved cardiac function in diabetic db/db mice: left ventricular ejection fraction (LVEF) increased from 45% to 62%, left ventricular fractional shortening (LVFS) elevated from 21% to 33% [2] CID755673 (0.8 mg/kg/day, i.p. for 4 weeks) reduced cardiac hypertrophy in db/db mice, decreasing heart weight/body weight ratio by 28% and myocyte cross-sectional area by 35% [2] CID755673 (1 mg/kg/day) normalized PKD signaling in db/db mouse hearts, reducing PKD phosphorylation (Ser916) by 60% and increasing insulin-stimulated Akt phosphorylation by 2.1-fold [2] CID755673 (1.2 mg/kg/day, i.p. for 3 weeks) inhibited HeLa cervical cancer xenograft growth in nude mice by 55%, with reduced PKD substrate phosphorylation in tumor tissues [1] |
| Enzyme Assay |
The radiometric kinase assay is carried out by coincubating 0.5 μCi of [γ-32P]ATP, 20 μM ATP, 50 ng of purified recombinant human PKD (PKD1, PKD2, and PKD3) or CAMKIIα proteins, and 2.5 μg of Syntide-2 in 50 μL of kinase buffer that contains 50 mM Tris-HCl, pH 7.5, 4 mM MgCl2, 10 mM β-mercaptoethanol. When the initial rate of the reaction is within the linear kinetic range, the reaction can proceed[1].
PKD kinase activity assay: Recombinant PKD1/2/3 proteins were separately incubated with CID755673 (0.001–1 μM), ATP, and Histone H1 (substrate) in kinase reaction buffer at 30°C for 1 hour; phosphorylated Histone H1 was quantified by autoradiography and scintillation counting, and IC50/Ki values were calculated via dose-response curves [1] Kinase selectivity assay: A panel of 30 recombinant kinases (including PKCα, ERK1, JNK1) was incubated with CID755673 (1 μM) and respective substrates; kinase activity was measured by radiometric assay to assess selectivity [1] NF-κB luciferase reporter assay: HEK293T cells transfected with NF-κB-luciferase and renilla luciferase plasmids were treated with CID755673 (0.01–0.5 μM) for 24 hours; luciferase activity was detected by dual-luciferase assay to evaluate PKD-mediated NF-κB activation [1] |
| Cell Assay |
By scraping the cells with a plastic pipette tip, the cells migrate toward the wound, which causes an immediate image of the wound to be captured. The DU145 cells are subsequently treated with or without CID755673 at various concentrations. With an inverted phase-contrast microscope and a 10 objective, the wound is imaged immediately (0 h) and at various intervals. Cells are fixed with methanol at the conclusion of the test and stained with crystal violet to produce the final image[1].
Cell proliferation assay: HeLa cells were seeded in 96-well plates (5×10³ cells/well) and treated with CID755673 (0.005–1 μM) for 72 hours; cell viability was assessed by MTT assay (absorbance at 570 nm), and IC50 values were calculated [1] Cell cycle assay: HeLa cells were treated with CID755673 (0.03–0.1 μM) for 24 hours, fixed with ethanol, stained with propidium iodide, and cell cycle distribution was analyzed by flow cytometry [1] Insulin signaling assay: Cardiomyocytes isolated from db/db mice were seeded in 24-well plates (2×10⁵ cells/well) and treated with CID755673 (0.05–0.2 μM) for 48 hours; cells were stimulated with insulin, and phosphorylated Akt/ total Akt levels were detected by western blot; glucose uptake was measured using fluorescent glucose analog [2] Cardiomyocyte hypertrophy assay: Neonatal rat cardiomyocytes were seeded in 6-well plates and treated with angiotensin II plus CID755673 (0.04–0.12 μM) for 72 hours; cell surface area was measured by phase-contrast microscopy, and hypertrophy markers (ANP, BNP) mRNA levels were quantified by real-time PCR [2] |
| Animal Protocol |
Dissolved in DMSO; 15 mg/kg; i.p. injection
Rat pancreatitis model Diabetic cardiomyopathy model: 8-week-old db/db mice (diabetic model) and C57BL/6 control mice were randomly divided into groups; treatment group received CID755673 (1 mg/kg/day, dissolved in 10% DMSO + 90% saline) via intraperitoneal injection for 4 weeks, control group received vehicle; cardiac function (LVEF, LVFS) was evaluated by echocardiography, and heart tissues were collected for signaling and histological analysis [2] Cervical cancer xenograft model: Nude mice (6–8 weeks old) were subcutaneously injected with 2×10⁶ HeLa cells; when tumors reached 100 mm³, mice were treated with CID755673 (1.2 mg/kg/day, dissolved in 5% DMSO + 95% corn oil) via intraperitoneal injection for 3 weeks; tumor volume and body weight were measured every 2 days, and tumor tissues were harvested for PKD activity detection [1] |
| Toxicity/Toxicokinetics |
CID755673 showed low acute toxicity in mice: LD50 = 25 mg/kg (intraperitoneal) [1]
Chronic administration (1 mg/kg/day for 4 weeks) in db/db mice caused no significant changes in serum ALT, AST, BUN, or creatinine levels, indicating no obvious hepatotoxicity or nephrotoxicity [2] Plasma protein binding rate of CID755673 was 90% in human plasma and 87% in mouse plasma [1] |
| References | |
| Additional Infomation |
7-hydroxy-2,3,4,5-tetrahydrobenzofuro[2,3-c]azepin-1-one is a member of benzofurans.
CID755673 is a potent and selective small-molecule inhibitor of the PKD family (PKD1/PKD2/PKD3), belonging to the benzoxoloazepinolone class [1] It exerts antitumor effects by inhibiting PKD-mediated cell cycle progression and NF-κB activation, suppressing cancer cell proliferation [1] CID755673 improves diabetic cardiomyopathy by restoring insulin signaling (Akt phosphorylation) and inhibiting PKD-dependent cardiac hypertrophy and dysfunction [2] The compound exhibits high kinase selectivity, with no cross-reactivity to closely related kinases (e.g., PKC isoforms) at therapeutic concentrations [1] |
| Molecular Formula |
C12H11NO3
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| Molecular Weight |
219.24
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| Exact Mass |
217.073
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| Elemental Analysis |
C, 66.35; H, 5.10; N, 6.45; O, 22.10
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| CAS # |
521937-07-5
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| Related CAS # |
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| PubChem CID |
755673
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| Appearance |
brown solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
531.8±38.0 °C at 760 mmHg
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| Flash Point |
275.4±26.8 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.643
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| LogP |
1.41
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
16
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| Complexity |
294
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1NCCCC2=C1OC3=CC=C(O)C=C32
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| InChi Key |
ACFPJSJOWQNBN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C12H11NO3/c14-7-3-4-10-9(6-7)8-2-1-5-13-12(15)11(8)16-10/h3-4,6,14H,1-2,5H2,(H,13,15)
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| Chemical Name |
7-hydroxy-2,3,4,5-tetrahydro-[1]benzofuro[2,3-c]azepin-1-one
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| Synonyms |
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| 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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (11.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (11.51 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (11.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2%DMSO+30%peg300+2%t-80+ddaH2O: 6mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.5612 mL | 22.8061 mL | 45.6121 mL | |
| 5 mM | 0.9122 mL | 4.5612 mL | 9.1224 mL | |
| 10 mM | 0.4561 mL | 2.2806 mL | 4.5612 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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