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]。