Voxelotor (GBT 440)是一种血红蛋白S (HbS) 聚合抑制剂，可改善镰状细胞病（SCD）的慢性溶血性贫血。
Cas No.:1446321-46-5
Sample solution is provided at 25 µL, 10mM.
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Voxelotor (GBT 440) is a haemoglobin S (HbS) polymerization inhibitor that improves the chronic hemolytic anemia of sickle cell disease (SCD)[1]. Voxelotor prevents HbS polymerization by bridging the two α-globin subunits together, stabilizing the hemoglobin in the ‘relaxed’ oxygenated configuration, thereby, increasing oxygen affinity and increasing the ratio of “oxy” HbS to deoxygenated HbS [2]. Voxelotor has been widely used to regulate the affinity of hemoglobin for oxygen, preventing the sickling of isolated red blood cells[3].
In vitro, Voxelotor treatment at 5mM for 2 hours can reverse the sickling of already sickled red blood cells under hypoxic conditions, and reduce the content of intracellular HbS polymers[4]. 1mM of Voxelotor treatment for 0.5h inhibited sickling of sickle cell trait blood under conditions mimicking a combination of hypoxia, dehydration and acidosis[5].
In vivo, Voxelotor was administered by gavage (200mg/kg) five times a week for three consecutive weeks, which significantly increased the hemoglobin (Hb) levels in the mice[6]. When oral administration of Voxelotor at a dose of 200mg/kg/day for two consecutive weeks, the Hb concentration in mice with SCD reached a steady state level of 802±81µM, and the p50 value (partial pressure of O2 at which Hb is 50% saturated) in the blood of SCD mice decreased from 39±0.8mmHg to 21±1.6mmHg[7]. Voxelotor treatment via oral administration at a dose of 150mg/kg (twice a day) for 12 days reduced the sickling in in whole blood of HbSS Townes knock-in sickle mice and increased Hb-O2 affinity[8].
References:
[1] Glaros A K, Razvi R, Shah N, et al. Voxelotor: alteration of sickle cell disease pathophysiology by a first-in-class polymerization inhibitor[J]. Therapeutic advances in hematology, 2021, 12: 20406207211001136.
[2] Jamalapur S L, Glaros A K, Ravindranath Y. Voxelotor (GBT440) in pediatric sickle cell disease: A review[J]. Pediatric Hematology Oncology Journal, 2024, 9(4): 244-249.
[3] Hutchaleelaha A, Patel M, Silva A, et al. GBT440 demonstrates high specificity for red blood cells in nonclinical species[J]. Blood, 2015, 126(23): 2172.
[4] Dufu K, Oksenberg D. GBT440 reverses sickling of sickled red blood cells under hypoxic conditions in vitro[J]. Hematology reports, 2018, 10(2): 7419.
[5] Dufu K, Lehrer-Graiwer J, Ramos E, et al. GBT440 inhibits sickling of sickle cell trait blood under in vitro conditions mimicking strenuous exercise[J]. Hematology reports, 2016, 8(3): 6637.
[6] Wang H, Miranda M, Marutani E, et al. Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α[J]. The Journal of Clinical Investigation, 2024, 134(23).
[7] Dufu K, Lucas A, Muller C R, et al. Pharmacological increase of Hb-O2 affinity with a voxelotor analog does not decrease brain tissue pO2 or limit O2 extraction in brain tissues of sickle cell mice[J]. Blood, 2019, 134: 3564.
[8] Oksenberg D, Dufu K, Patel M P, et al. GBT 440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half‐life in a murine model of sickle cell disease[J]. British journal of haematology, 2016, 175(1): 141-153.
Voxelotor (GBT 440)是一种血红蛋白S (HbS) 聚合抑制剂，可改善镰状细胞病（SCD）的慢性溶血性贫血[1]。Voxelotor通过桥接两个α-globin亚基，将血红蛋白稳定在“松弛”的氧合构象中，从而阻止HbS聚合，增加氧亲和力并提高“氧合”HbS与脱氧HbS的比例[2]。Voxelotor已被广泛用于调节血红蛋白对氧的亲和力，以防止分离红细胞的镰变[3]。
在体外，用5mM的Voxelotor处理缺氧条件下已镰变的红细胞2小时，可逆转镰变，并减少细胞内HbS 聚合物的含量[4]。在模拟缺氧、脱水和酸中毒组合条件下，用1mM的Voxelotor处理镰状细胞性状血液0.5小时，可抑制镰变[5]。
在体内，通过灌胃给予Voxelotor (200mg/kg)，每周五次，连续三周，可显著增加小鼠的血红蛋白(Hb)水平[6]。当连续两周以200mg/kg/day的剂量口服Voxelotor时，镰状细胞病小鼠的Hb浓度达到稳态水平802±81µM，SCD小鼠血液中的p50值（Hb达到50%饱和度时的氧分压）从39±0.8mmHg降至21±1.6mmHg [7]。以 150mg/kg的剂量口服Voxelotor（每日两次），连续12天，可减少HbSS Townes knock-in sickle小鼠全血中的镰变，并增加Hb-O2亲和力[8]。
| Cell experiment [1]: | |
Cell lines | Sickle red blood cells |
Preparation Method | 500µl of PBS (pH 7.4; isotonic) was added to sickle red blood cells (500µl) and centrifuged at 250g for 5min. After centrifugation, the supernatant was discarded. 20µl of packed sickle red blood cells was added to 30µl of PBS in a 96-well gas permeable plate and incubated for 0.5 hours at 37℃ in a humidified hypoxic chamber (4% O2; 96% N2). Voxelotor (in 100% DMSO) was added to 50µl of deoxygenated-PBS at varying concentrations. DMSO alone was used as acontrol. Next, sickle red blood cells (50µl) were added to 50µl of Voxelotor solution and mixed. The final Voxelotor concentrations were 0, 1mM, 2mM, and 5mM and the final DMSO concentration was 2.5% per reaction. The reaction mixture was incubated under continued hypoxia for an additional 2 hours. Next, cells were imaged using a bright-field microscope fitted with a camera in the hypoxic chamber. Images (40×magnification) were quantified by manually counting round cells versus ill-shaped cells (sickled cells). |
Reaction Conditions | 0, 1mM, 2mM, and 5mM; 2h |
Applications | Voxelotor treatment reversed sickling of already sickled red blood cells under hypoxic conditions in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | HbSS Townes knock-in sickle mice |
Preparation Method | The HbSS Townes knock-in sickle mice were kept in temperature-controlled (21°C-25°C) and humidity-maintained (40%-70%) room with a 12h light/dark cycle. Water and food were provided freely. Voxelotor [150mg/kg in 0.5% methylcellulose/0.5% Sodium Dodecyl Sulfate (SDS)] was administered twice daily by oral gavage for 12 days. Blood samples (50μl) for sickling measurements were collected 4h following the last dose of the chronic regimen. |
Dosage form | 150mg/kg; twice a day for 12 days; p.o. |
Applications | Voxelotor treatment reduced sickling in whole blood of HbSS Townes knock-in sickle mice. |
References: | |
| Cas No. | 1446321-46-5 | SDF | |
| 别名 | 沃塞洛托,GBT 440 | ||
| Canonical SMILES | OC1=CC=CC(OCC2=C(C3=CC=NN3C(C)C)N=CC=C2)=C1C=O | ||
| 分子式 | C19H19N3O3 | 分子量 | 337.37 |
| 溶解度 | DMSO : ≥ 125 mg/mL (370.51 mM) | 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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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.9641 mL | 14.8205 mL | 29.641 mL |
| 5 mM | 592.8 μL | 2.9641 mL | 5.9282 mL |
| 10 mM | 296.4 μL | 1.4821 mL | 2.9641 mL |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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