GBT-440 - CAS 1446321-46-5
Catalog number: B0084-474581
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
GBT-440 is a substituted benzaldehyde compound that can modulate sickle hemoglobin (HbS) for treatment of disorders.
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Catalog Number Size Price Stock Quantity
B0084-474581 100 mg $288 In stock
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Solid Powder
Voxelotor, GBT-440, GBT 440, GBT440, GTx-011, GTx011, GTx 011; 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde; Hemoglobin Modulators-1
Soluble in DMSO
Store in a cool and dry place and at 0 - 4℃ for short term (days to weeks) or -59℃ for long term (months to years).
Boiling Point:
539.2±50.0 °C | Condition: Press: 760 Torr
1.23±0.1 g/cm3
Canonical SMILES:
1.GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.
Oksenberg D;Dufu K;Patel MP;Chuang C;Li Z;Xu Q;Silva-Garcia A;Zhou C;Hutchaleelaha A;Patskovska L;Patskovsky Y;Almo SC;Sinha U;Metcalf BW;Archer DR Br J Haematol. 2016 Oct;175(1):141-53. doi: 10.1111/bjh.14214. Epub 2016 Jul 5.
A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease-modifying agent in sickle cell patients.
2.Impact of voxelotor (GBT440) on unconjugated bilirubin and jaundice in sickle cell disease.
Telfer P;Agodoa I;Fox KM;Burke L;Mant T;Jurek M;Tonda M;Lehrer-Graiwer J Hematol Rep. 2018 May 22;10(2):7643. doi: 10.4081/hr.2018.7643. eCollection 2018 May 14.
For many patients with sickle cell disease (SCD), jaundice is a significant clinical disease manifestation that impacts on patient well-being. We report a case of a patient with SCD and chronic jaundice treated with voxelotor (GBT440), a novel small molecule hemoglobin oxygen affinity modulator and potential disease-modifying therapy for SCD. The case patient is a 27-year-old Black male with a long history of SCD with clinical jaundice and scleral icterus. After starting voxelotor, the patient reported that his jaundice cleared within one week, and that he felt much better with more energy, and was relieved after his eyes cleared. Voxelotor reduced bilirubin and unconjugated bilirubin (by up to 76%), and hemoglobin improved from 9.9 g/dL at baseline to 11.1 g/dL at 90 days. Jaundice impacts many adults with SCD, significantly impacting self-image. Voxelotor treatment reduced bilirubin levels and improved jaundice, resulting in an improved sense of well-being in our case patient.
3.Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease.
Li Q;Henry ER;Hofrichter J;Smith JF;Cellmer T;Dunkelberger EB;Metaferia BB;Jones-Straehle S;Boutom S;Christoph GW;Wakefield TH;Link ME;Staton D;Vass ER;Miller JL;Hsieh MM;Tisdale JF;Eaton WA Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):E689-E696. doi: 10.1073/pnas.1619054114. Epub 2017 Jan 17.
Although it has been known for more than 60 years that the cause of sickle cell disease is polymerization of a hemoglobin mutant, hydroxyurea is the only drug approved for treatment by the US Food and Drug Administration. This drug, however, is only partially successful, and the discovery of additional drugs that inhibit fiber formation has been hampered by the lack of a sensitive and quantitative cellular assay. Here, we describe such a method in a 96-well plate format that is based on laser-induced polymerization in sickle trait cells and robust, automated image analysis to detect the precise time at which fibers distort ("sickle") the cells. With this kinetic method, we show that small increases in cell volume to reduce the hemoglobin concentration can result in therapeutic increases in the delay time prior to fiber formation. We also show that, of the two drugs (AES103 and GBT440) in clinical trials that inhibit polymerization by increasing oxygen affinity, one of them (GBT440) also inhibits sickling in the absence of oxygen by two additional mechanisms.;TRIAL REGISTRATION: ; ;NCT02380079;.
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CAS 1446321-46-5 GBT-440

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