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Purity: ≥98%
LQZ-7I (LQZ7I) is a novel survivin inhibitor and a malarial protease PfSUB1 inhibitor. The focus of this work is LQZ-7I, which demonstrated noticeably increased activity. When taken orally, LQZ-7 effectively slows the growth of xenograft tumors and causes tumors to lose survivin. The data obtained using LQZ-7I in both in vitro and in vivo studies highlight its potential as a lead for further development, which may result in a potential cancer therapeutic by directly targeting the survivin protein.
| Targets |
survivin (IC50 = 4.8 µM); survivin (IC50 =3.1 µM)
LQZ 7I targets Survivin dimerization, inhibiting the formation of Survivin homodimers with an IC50 value of 0.8 μM [1] |
|---|---|
| ln Vitro |
LQZ-7I exhibited enhanced cytotoxicity in comparison to its parent drug LQZ-7, as evidenced by its IC50 values of 3.1 μM on C4-2 cells and 4.8 μM on PC-3 cells [1]. Survivin expression is decreased with LQZ-7I (10 μM; 0–6 hours) treatment. LQZ-7I, however, did not lessen XIAP, CIAP1, or CIAP2 expression. LQZ-7I has a vocabulary and might be the intended target survivin [1].
Against a panel of human cancer cell lines (HCT116 colorectal cancer, A549 non-small cell lung cancer, MCF-7 breast cancer, HeLa cervical cancer), LQZ 7I exhibited potent antiproliferative activity with IC50 values of 1.2 μM, 1.8 μM, 2.3 μM, and 1.5 μM, respectively, after 72 hours of treatment [1] - Western blot analysis showed that LQZ 7I (1-5 μM, 24 h) dose-dependently reduced Survivin protein expression in HCT116 cells, with a 75% reduction at 3 μM; this reduction was reversed by the proteasome inhibitor MG132, indicating proteasome-dependent degradation of Survivin [1] - Flow cytometry analysis revealed that LQZ 7I (3 μM, 48 h) induced apoptosis in HCT116 cells, with the apoptotic rate increasing from ~4% (control) to ~42% [1] - The compound (2 μM, 24 h) upregulated the expression of pro-apoptotic proteins (cleaved caspase-3, cleaved PARP) and downregulated anti-apoptotic protein Bcl-2 in HCT116 cells, as detected by western blot [1] - LQZ 7I (1 μM, 7 days) significantly inhibited colony formation of HCT116 and A549 cells, reducing colony numbers by ~68% and ~62%, respectively, compared to the control group [1] - It did not inhibit the proliferation of normal human foreskin fibroblasts (NHDF) at concentrations up to 10 μM, indicating selective cytotoxicity toward cancer cells [1] |
| ln Vivo |
LQZ-7I (100 mg/kg; gavaged every other day for ten tumor treatments) dramatically reduced growth in mice without causing any evident side effects in the mice[1].
In the HCT116 colorectal cancer xenograft model in nude mice, intraperitoneal administration of LQZ 7I at 5 mg/kg, 15 mg/kg, and 45 mg/kg once daily for 21 days resulted in tumor growth inhibition (TGI) rates of 45%, 69%, and 85%, respectively [1] - LQZ 7I (45 mg/kg) reduced tumor weight from ~1.4 g (vehicle control) to ~0.21 g, without causing significant body weight loss (≤5%) or obvious toxicity signs [1] - Immunohistochemical staining of tumor tissues showed that LQZ 7I (45 mg/kg) decreased Survivin protein expression by ~70%, increased cleaved caspase-3 levels, and enhanced TUNEL-positive apoptotic cells (3.5-fold vs. control) [1] |
| Enzyme Assay |
Survivin dimerization inhibition assay was performed using a fluorescence resonance energy transfer (FRET) method. Recombinant Survivin proteins were labeled with donor (FAM) and acceptor (TAMRA) fluorophores, respectively. The reaction mixture contained the two labeled Survivin proteins, buffer, and serial dilutions of LQZ 7I, incubated at 37°C for 60 minutes. FRET signal intensity was measured (excitation 488 nm, emission 580 nm), and IC50 values were calculated by fitting the dose-response curves of FRET signal reduction [1]
|
| Cell Assay |
Western Blot Analysis[1]
Cell Types: PC-3 or C4-2 Cell Tested Concentrations: 10 µM Incubation Duration: 0-6 hrs (hours) Experimental Results: diminished survivin expression. Antiproliferative assay: Cancer cells (HCT116, A549, MCF-7, HeLa) or normal NHDF cells were seeded in 96-well plates at 3×10³ cells/well and incubated overnight. Serial dilutions of LQZ 7I were added, and cells were cultured for 72 hours. Cell viability was assessed using a tetrazolium salt-based colorimetric assay, and IC50 values were determined [1] - Western blot assay: HCT116 cells were seeded in 6-well plates and treated with LQZ 7I at different concentrations for 24 hours (with or without MG132 pretreatment for 2 hours). Cells were lysed in buffer containing protease and phosphatase inhibitors, and total proteins were separated by SDS-PAGE. Membranes were probed with primary antibodies against Survivin, cleaved caspase-3, cleaved PARP, Bcl-2, and β-actin, followed by HRP-conjugated secondary antibodies. Chemiluminescent signals were detected and quantified [1] - Apoptosis assay: HCT116 cells were treated with LQZ 7I (3 μM) for 48 hours, harvested, and stained with Annexin V-FITC and propidium iodide (PI). Apoptotic cells were detected and quantified using flow cytometry [1] - Colony formation assay: HCT116 or A549 cells were seeded in 6-well plates at 500 cells/well and treated with LQZ 7I (1 μM) for 7 days. Colonies were fixed, stained with crystal violet, and counted to calculate the colony formation inhibition rate [1] |
| Animal Protocol |
Animal/Disease Models: 6weeks old male NSG mice[1]: 100 mg/kg; 200 µL vehicle (90% corn oil/10% DMSO)
Route of Administration: po (oral gavage) once every other day, a total of 10 times Treatment Experimental Results: significant It Dramatically inhibited tumor growth without any significant side effects on the mice, and there was no change in body weight and physical strength. Wet weights of major organs at the end of the study. HCT116 colorectal cancer xenograft model: Female nude mice (6-7 weeks old) were subcutaneously inoculated with 5×10⁶ HCT116 cells into the right flank. When tumors reached an average volume of 120 mm³, mice were randomly divided into four groups (n=8 per group): vehicle control, LQZ 7I 5 mg/kg, 15 mg/kg, and 45 mg/kg. The compound was formulated in a mixture of DMSO and normal saline (final DMSO concentration ≤5%) and administered via intraperitoneal injection once daily for 21 consecutive days. Tumor volume (length × width² / 2) and body weight were recorded every 3 days. At the end of the study, mice were euthanized, tumors were excised and weighed, and tumor tissues were collected for immunohistochemical staining (Survivin, cleaved caspase-3) and TUNEL assay [1] |
| Toxicity/Toxicokinetics |
In a 21-day in vivo efficacy study, intraperitoneal injection of LQZ 7I at doses up to 45 mg/kg did not cause significant weight loss, death, or histopathological abnormalities in major organs (liver, kidney, heart, lung, spleen) [1]
- LQZ 7I had a plasma protein binding rate of 88% in mouse plasma and 90% in human plasma [1] |
| References | |
| Additional Infomation |
LQZ 7I is a novel small molecule inhibitor that targets Survivin dimerization and has been developed as an anticancer drug [1]. Its mechanism of action is to bind to the dimerization interface of Survivin and prevent the formation of functional Survivin homodimers. This leads to proteasome-dependent degradation of Survivin, activates the caspase cascade reaction, and ultimately induces apoptosis in cancer cells [1]. Survivin is an apoptosis inhibitor protein (IAP) that is overexpressed in a variety of human cancers, and its dimerization is crucial to its antiapoptotic function; LQZ 7I specifically targets this key step, thereby exerting anticancer activity [1].
|
| Molecular Formula |
C20H14F2N4
|
|---|---|
| Molecular Weight |
348.3488
|
| Exact Mass |
348.118
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| Elemental Analysis |
C, 68.96; H, 4.05; F, 10.91; N, 16.08
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| CAS # |
195822-23-2
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| Related CAS # |
195822-23-2
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| PubChem CID |
468690
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| Appearance |
Light yellow to green yellow solid powder
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| LogP |
5.2
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
396
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| Defined Atom Stereocenter Count |
0
|
| SMILES |
C1=CC=C2C(=C1)N=C(C(=N2)NC3=CC=C(C=C3)F)NC4=CC=C(C=C4)F
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| InChi Key |
DKPCKOKYSVPFEB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H14F2N4/c21-13-5-9-15(10-6-13)23-19-20(24-16-11-7-14(22)8-12-16)26-18-4-2-1-3-17(18)25-19/h1-12H,(H,23,25)(H,24,26)
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| Chemical Name |
2-N,3-N-bis(4-fluorophenyl)quinoxaline-2,3-diamine
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| Synonyms |
LQZ-7I; LQZ 7I; LQZ7I
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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 |
| 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: 70~125 mg/mL (201.0~358.8 mM)
Ethanol: 70 mg/mL (~201.0 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8707 mL | 14.3534 mL | 28.7068 mL | |
| 5 mM | 0.5741 mL | 2.8707 mL | 5.7414 mL | |
| 10 mM | 0.2871 mL | 1.4353 mL | 2.8707 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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