<scp>GBT</scp>440 increases haemoglobin oxygen affinity, reduces sickling and prolongs <scp>RBC</scp> half‐life in a murine model of sickle cell disease

Oksenberg, Donna; Dufu, Kobina; Patel, Mira; Chuang, Chih-Yuan; Li, Zhe; Xu, Qing; Silva-García, Abel; Zhou, Chengjing; Hutchaleelaha, Athiwat; Patskovska, L.N.; Patskovsky, Y.; Almo, Steven C.; Sinha, U. S. P.; Metcalf, Brian W.; Archer, David

doi:10.1111/bjh.14214

Cited by 203 publications

(276 citation statements)

References 41 publications

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“…The other is 2-hydroxy-6((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde) (called GBT440; ClinicalTrials.gov identifier NCT02285088; ref. 40). Both compounds are believed to inhibit sickling in vivo primarily by increasing oxygen affinity because of preferential binding to the high-affinity R quaternary structure, which does not enter the fiber (13, 29) (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Henry

Hofrichter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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.sickle cell | drugs | hemoglobin S | treatment | screening assay

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Section: Resultsmentioning

confidence: 99%

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Henry

Hofrichter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…23,24 However, there are few stroke models in sickle mice. 12–14 Our results suggest two stroke models based on hypoxic-ischemic insults in sickle mice that may relate to SCA patients, in whom the same insult often leads to an imbalance of oxygen consumption and oxygen delivery in the brain.…”

Section: Discussionmentioning

confidence: 99%

Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment

Sun

Lee

Huang

et al. 2017

Stroke

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Background and Purpose The effects of lytic stroke therapy in patients with sickle cell anemia (SCA) are unknown, although a recent study suggested that co-existent SCA does not increase the risk of cerebral hemorrhage. This finding calls for systemic analysis of the effects of thrombolytic stroke therapy, first in humanized sickle mice, then in patients. There is also a need for additional predictive markers of SCA-associated vasculopathy. Methods We used Doppler ultrasound to examine the carotid artery of Townes sickle mice tested their responses to repetitive-mild hypoxia-ischemia (rmHI) and transient hypoxia-ischemia (tHI)-induced stroke at three or six months of age, respectively. We also examined the effects of tissue-plasminogen activator (tPA) treatment in tHI-injured sickle mice. Results Three-month-old SS mice showed elevated resistive index (RI) in the carotid artery and higher sensitivity to rmHI-induced cerebral infarct. Six-month-old SS mice showed greater RI and increased flow velocity without obstructive vasculopathy in the carotid artery. Instead, the cerebral vascular wall in SS mice showed ectopic expression of Plasminogen Activator Inhibitor-1 (PAI-1) and P-Selectin, suggesting a pro-adhesive and pro-thrombotic propensity. Indeed, SS mice showed enhanced leukocyte and platelet adherence to the cerebral vascular wall, broader fibrin deposition, and higher mortality after tHI. Yet, post-tHI treatment with tPA reduced thrombosis and mortality in SS mice. Conclusions Sickle mice are sensitive to hypoxia/ischemia-induced cerebral infarct, but benefit from thrombolytic treatment. An increased resistive index in carotid arteries may be an early marker of sickle cell vasculopathy.

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“…Such structural modifications have been shown in vanillin derivatives to stabilize the Schiff-base interaction between the aromatic aldehyde and the protein to improve their pharmacologic profiles. 16,17 …”

Section: Discussionmentioning

confidence: 99%

“…6,11–15 Consistently, the synthetic derivatives, such as Tucaresol and GBT-440, with apparent increased protein interactions have demonstrated both enhanced potency and improved pharmacokinetic properties than the parent vanillin. 13,16,17 Unlike the above-mentioned aromatic aldehydes, there are other classes of aromatic aldehydes that bind Hb and preferentially stabilize the T-state relative to the R-state resulting in a decrease in Hb affinity for oxygen. 11,12,25,26 These compounds as expected promote sickling.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Ester and Ether Derivatives of Antisickling Agent 5-HMF for the Treatment of Sickle Cell Disease

Xu¹,

Pagare²,

Ghatge³

et al. 2017

Mol. Pharmaceutics

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Candidate drugs to counter intracellular polymerization of deoxygenated sickle hemoglobin (Hb S) continue to represent a promising approach to mitigating the primary cause of the pathophysiology associated with sickle cell disease (SCD). One such compound is the naturally occurring antisickling agent, 5-hydroxymethyl-2-furfural (5-HMF), which has been studied in the clinic for the treatment of SCD. As part of our efforts to develop novel efficacious drugs with improved pharmacologic properties, we structurally modified 5-HMF into 12 ether and ester derivatives. The choice of 5-HMF as a pharmacophore was influenced by a combination of its demonstrated attractive hemoglobin modifying and antisickling properties, well-known safety profiles, and its reported nontoxic major metabolites. The derivatives were investigated for their time- and/or dose-dependent effects on important antisickling parameters, such as modification of hemoglobin, corresponding changes in oxygen affinity, and inhibition of red blood cell sickling. The novel test compounds bound and modified Hb and concomitantly increased the protein affinity for oxygen. Five of the derivatives exhibited 1.5- to 4.0-fold higher antisickling effects than 5-HMF. The binding mode of the compounds with Hb was confirmed by X-ray crystallography and, in part, helps explain their observed biochemical properties. Our findings, in addition to the potential therapeutic application, provide valuable insights and potential guidance for further modifications of these (and similar) compounds to enhance their pharmacologic properties.

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GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half‐life in a murine model of sickle cell disease

Cited by 203 publications

References 41 publications

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment

Design, Synthesis, and Biological Evaluation of Ester and Ether Derivatives of Antisickling Agent 5-HMF for the Treatment of Sickle Cell Disease

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