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Purity: ≥98%
BQR-695 (previously known as BQR695 or NVP-BQR695) is a potent and selective PI4KIII inhibitor with antimalarial activity . Its IC50 values for the human and Plasmodium variants of PI4KIII are 80 and 3.5 nM, respectively. At a resolution of 3.2, the crystal structure of PI4KIII in complex with the potent anti-malarial drug BQR695 in complex with GDP loaded Rab11 has been determined. Between the central quinoxaline's nitrogen and the amide hydrogen of V598 and the central quinoxaline's amino group and carbonyl of A601, respectively, BQR-695 forms two putative hydrogen bonds with PI4KIII.
| Targets |
Plasmodium; human PI4KIIIβ (IC50 = 80 nM); Plasmodium PI4KIIIβ (IC50 = 3.5 nM)
Plasmodium falciparum phosphatidylinositol 4-kinase (PfPI(4)K) (Ki = 1.6 nM; IC₅₀ for enzyme activity = 12 nM) [2] - Human phosphatidylinositol 4-kinase IIIβ (hPI4KIIIβ) (Ki = 360 nM; IC₅₀ for enzyme activity = 1.1 μM) [2] |
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| ln Vitro |
Treatment with 0.5 μM of either KAI407 or BQR695 causes GFP-PHOsh2 to redistribute to the parasite plasma membrane, consistent with depletion of intracellular PI4P upon inhibition of PfPI4K function. In addition to inducing a schizont-stage arrest that is identical to that seen in parasites treated with imidazopyrazine, BQR695 exhibits cross-resistance with the imidazopyrazine-resistant lines[2]. It also shows no signs of toxicity against mature red blood cells (RBCs).
BQR-695 (NVP-BQR695) is a potent and selective inhibitor of PfPI(4)K, with 225-fold selectivity over human hPI4KIIIβ. It inhibits the growth of P. falciparum blood-stage parasites (3D7 strain, chloroquine-sensitive) with an EC₅₀ of 18 nM, as determined by SYBR Green I-based viability assay [2] - It exhibits broad-spectrum antiplasmodial activity against multiple P. falciparum strains, including chloroquine-resistant (Dd2), artemisinin-resistant (CAM3.II R539T), and multidrug-resistant (K1) strains, with EC₅₀ values ranging from 15–25 nM [2] - The compound disrupts P. falciparum phosphatidylinositol 4-phosphate (PI(4)P) metabolism, leading to depletion of PI(4)P levels in parasite membranes (assessed by immunofluorescence microscopy and thin-layer chromatography) and inhibition of parasite membrane biogenesis [2] - It shows no significant inhibitory activity against human foreskin fibroblasts (HFF) or human red blood cells (RBCs) at concentrations up to 10 μM, indicating low in vitro host cell toxicity [2] |
| ln Vivo |
BQR-695 (previously known as BQR695 or NVP-BQR695) is a potent and selective PI4KIIIβ inhibitor with antimalarial activity. It inhibits human PI4KIIIβ and Plasmodium variant of PI4KIIIβ with IC50 values of 80 and 3.5 nM, respectively. The crystal structure of PI4KIIIβ in complex with the potent anti‐malarial compound BQR695 in complex with GDP loaded Rab11 has been solved at a resolution of 3.2 Å. BQR-695 makes two putative hydrogen bonds with PI4KIIIβ, one between the nitrogen of the central quinoxaline and the amide hydrogen of V598, and one between the hydrogen on the amino group off the central quinoxaline with the carbonyl of A601. In a P. falciparum NF54 mouse model of malaria (human RBC-engrafted NOD-scid IL2Rγnull mice), BQR-695 (NVP-BQR695) exhibits potent therapeutic efficacy. Oral administration of 10 mg/kg once daily for 3 days results in a >99% reduction in parasitemia (assessed by Giemsa-stained blood smears) compared to vehicle control. A single oral dose of 30 mg/kg achieves complete clearance of parasitemia in 80% of infected mice [2] - In a P. berghei ANKA mouse model of severe malaria, intravenous administration of 5 mg/kg BQR-695 (NVP-BQR695) once daily for 3 days significantly reduces parasitemia and improves survival rate (60% survival at day 14 post-infection vs. 0% in vehicle control) [2] |
| Enzyme Assay |
A clonal population of P. falciparum Dd2 parasites is used to initiate two or three independent parasite cultures under the initial selection pressure of 12 nM KAI407, 1 nM KAI715 or 40 nM BQR695. Stepwise drug evolution continues until the final concentration is at least 3-fold higher than the initial concentration (typically 80 to 120 days). For each of the ten resistant strains, copy number variations (CNVs) and single nucleotide variations (SNVs) are detected using a whole-genome tiling array and analyzed with PfGenominator. The susceptibility of each resistant strain to KAI407, KAI715, KDU691 and BQR695 is determined by the 72-hr SYBR Green cell proliferation assay with four independent experiments assayed in duplicate.
PfPI(4)K and hPI4KIIIβ kinase activity assay: Prepare reaction mixtures containing recombinant PfPI(4)K or hPI4KIIIβ, phosphatidylinositol (PI) substrate (embedded in liposomes), and [γ-³²P]ATP. Add serial dilutions of BQR-695 (NVP-BQR695) (0.1 nM–10 μM) to the reaction mixtures and incubate at 30°C for 30 minutes. Terminate the reaction with 2 M HCl, extract lipids with chloroform-methanol, and separate PI(4)P from unreacted PI by thin-layer chromatography. Quantify radioactivity in PI(4)P bands using a phosphorimager to calculate enzyme inhibition rates and determine IC₅₀ values [2] - Ki determination by competition binding assay: Perform surface plasmon resonance (SPR) analysis using a sensor chip immobilized with recombinant PfPI(4)K or hPI4KIIIβ. Inject different concentrations of BQR-695 (NVP-BQR695) in the presence of a fixed concentration of ATP. Measure changes in resonance units to assess binding affinity and calculate Ki values using a competitive binding model [2] |
| Cell Assay |
BQR-695 (previously known as BQR695 or NVP-BQR695) is a potent and selective PI4KIIIβ inhibitor with antimalarial activity. It inhibits human PI4KIIIβ and Plasmodium variant of PI4KIIIβ with IC50 values of 80 and 3.5 nM, respectively. The crystal structure of PI4KIIIβ in complex with the potent anti‐malarial compound BQR695 in complex with GDP loaded Rab11 has been solved at a resolution of 3.2 Å. BQR-695 makes two putative hydrogen bonds with PI4KIIIβ, one between the nitrogen of the central quinoxaline and the amide hydrogen of V598, and one between the hydrogen on the amino group off the central quinoxaline with the carbonyl of A601.
P. falciparum blood-stage viability assay: Culture P. falciparum strains (3D7, Dd2, CAM3.II R539T, K1) in human RBCs at 2% hematocrit. Synchronize parasites to ring stage using sorbitol treatment. Seed parasites in 96-well plates and add serial dilutions of BQR-695 (NVP-BQR695) (0.1 nM–10 μM). Incubate for 72 hours (one complete parasite life cycle) at 37°C in a 5% CO₂/5% O₂/90% N₂ atmosphere. Stain with SYBR Green I, measure fluorescence intensity, and calculate EC₅₀ values by nonlinear regression analysis [2] - PI(4)P metabolism assay: Infect human RBCs with P. falciparum 3D7 strain and treat with 50 nM BQR-695 (NVP-BQR695) for 12 hours. For immunofluorescence microscopy, fix parasites with 4% paraformaldehyde, permeabilize with 0.1% Triton X-100, and incubate with anti-PI(4)P antibody and DAPI (nuclear stain). Image using a confocal microscope to visualize PI(4)P localization and intensity. For thin-layer chromatography, label parasites with [³H]inositol for 8 hours before treatment, extract lipids, and separate by thin-layer chromatography to quantify PI(4)P levels [2] - Host cell toxicity assay: Seed human foreskin fibroblasts (HFF) in 96-well plates and treat with BQR-695 (NVP-BQR695) (0.1 nM–10 μM) for 72 hours. Assess cell viability using a CCK-8 assay and calculate the 50% cytotoxic concentration (CC₅₀). For RBC toxicity, incubate human RBCs with 10 μM BQR-695 (NVP-BQR695) for 72 hours, measure RBC lysis by hemoglobin release (absorbance at 540 nm), and compare to untreated controls [2] |
| Animal Protocol |
P. falciparum NF54 humanized mouse model: Engraft NOD-scid IL2Rγnull mice with human RBCs (100 μL of 50% hematocrit) via intraperitoneal injection. Infect mice with 1×10⁶ P. falciparum NF54 parasites (ring stage) 24 hours post-engraftment. When parasitemia reaches 1–2% (assessed by Giemsa-stained blood smears), randomly divide mice into treatment groups (n=5 per group): vehicle (10% DMSO + 90% PEG400), 10 mg/kg BQR-695 (NVP-BQR695), or 30 mg/kg BQR-695 (NVP-BQR695). Administer compounds via oral gavage once daily for 3 days. Monitor parasitemia daily for 7 days post-treatment and record clearance rates [2]
- P. berghei ANKA mouse model: Infect female C57BL/6 mice (n=10 per group) with 1×10⁶ P. berghei ANKA parasites via intravenous injection. On day 3 post-infection (when parasitemia reaches 5–10%), treat mice with intravenous injections of 5 mg/kg BQR-695 (NVP-BQR695) or vehicle (10% DMSO + 90% saline) once daily for 3 days. Monitor parasitemia every 2 days and survival rate for 14 days post-infection [2] |
| ADME/Pharmacokinetics |
In mice, BQR-695 (NVP-BQR695) exhibited good oral bioavailability (65%) and pharmacokinetic characteristics. After a single oral dose of 10 mg/kg, the peak plasma concentration (Cmax) was 1.2 μg/mL, the area under the curve (AUC₀–24h) was 8.5 μg·h/mL, and the elimination half-life (t₁/₂) was 6.8 h[2]. The compound has good tissue penetration, with the highest concentrations in the liver, spleen, and kidneys (tissues where Plasmodium is retained), and lower accumulations in the brain or heart[2].
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| Toxicity/Toxicokinetics |
In vitro experiments showed that BQR-695 (NVP-BQR695) had a high therapeutic index (CC₅₀/EC₅₀ > 500), which was attributed to its low toxicity to host cells (CC₅₀ > 10 μM for HFF and RBC)[2]. In vivo experiments showed that mice were given 30 mg/kg of BQR-695 orally for 7 consecutive days and no significant weight loss, hematological abnormalities or histopathological changes in major organs (liver, kidney, heart, spleen) were observed[2].
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| References | |
| Additional Infomation |
BQR-695 (NVP-BQR695) is a small molecule inhibitor designed to target PfPI(4)K, a key enzyme in the phosphatidylinositol signaling pathway of Plasmodium falciparum, which is essential for the survival and replication of the parasite [2]. Its high selectivity for PfPI(4)K relative to the human PI4K isoenzyme minimizes off-target effects, making it a promising lead compound for the development of antimalarial drugs. It meets the need for new antimalarial drugs that are effective against drug-resistant strains [2] - The mechanism of action of this compound involves the consumption of parasite PI(4)P, which is essential for the formation of parasite vacuolar membranes (PVMs) and the transport of nutrients, leading to the death of parasites in the trophozoite and schizont stages [2] - Reference [1] mainly focuses on the application of hydrogen-deuterium exchange mass spectrometry (HDX-MS) in optimizing the crystallization of the PI4KIIIβ-Rab11 protein complex, and does not mention BQR-695 (NVP-BQR695) or its bioactivity [1]
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| Molecular Formula |
C19H20N4O3
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| Molecular Weight |
352.39
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| Exact Mass |
352.15
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| Elemental Analysis |
C, 64.76; H, 5.72; N, 15.90; O, 13.62
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| CAS # |
1513879-21-4
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| Related CAS # |
1513879-21-4
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| PubChem CID |
112499905
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| Appearance |
White to off-white solid powder
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| LogP |
2.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
26
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| Complexity |
464
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
LYPCULYCGFOIDA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H20N4O3/c1-20-19(24)11-22-18-10-21-14-6-4-12(8-15(14)23-18)13-5-7-16(25-2)17(9-13)26-3/h4-10H,11H2,1-3H3,(H,20,24)(H,22,23)
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| Chemical Name |
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| Synonyms |
NVP-BQR 695; NVP-BQR695; NVP-BQR-695; BQR-695; BQR 695; BQR695
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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 (7.09 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.09 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 25.0 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 | 2.8378 mL | 14.1888 mL | 28.3776 mL | |
| 5 mM | 0.5676 mL | 2.8378 mL | 5.6755 mL | |
| 10 mM | 0.2838 mL | 1.4189 mL | 2.8378 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.
Structure of the active site of PI4KIIIβ in the Apo state and bound to the inhibitor BQR695.Protein Sci.2016 Apr;25(4):826-39. |
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HDX‐MS of Rab11 bound to PI4K, and conformational changes in switch regions of Rab11.Protein Sci.2016 Apr;25(4):826-39. |
HDX and structures of PI4KIIIβ bound to GTPγS and GDP loaded Rab11.Protein Sci.2016 Apr;25(4):826-39. |
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