Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

Brian Metcalf; Chihyuan Chuang; Kobina Dufu; Mira P. Patel; Abel Silva-Garcia; Carl Johnson; Qing Lu; James R. Partridge; Larysa Patskovska; Yury Patskovsky; Steven C. Almo; Matthew P. Jacobson; Lan Hua; Qing Xu; Stephen L. Gwaltney; Calvin Yee; Jason Harris; Bradley P. Morgan; Joyce James; Donghong Xu; Athiwat Hutchaleelaha; Kumar Paulvannan; Donna Oksenberg; Zhe Li

doi:10.1021/acsmedchemlett.6b00491

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

Brian Metcalf, Chihyuan Chuang, Kobina Dufu, Mira P. Patel, Abel Silva-Garcia, Carl Johnson, Qing Lu, James R. Partridge, Larysa Patskovska, Yury Patskovsky, Steven C. Almo, Matthew P. Jacobson, Lan Hua, Qing Xu, Stephen L. Gwaltney, Calvin Yee, Jason Harris, Bradley P. Morgan, Joyce James, Donghong XuAthiwat Hutchaleelaha, Kumar Paulvannan, Donna Oksenberg, Zhe Li

Biochemistry

Research output: Contribution to journal › Article

35 Scopus citations

Abstract

We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).

Original language	English (US)
Pages (from-to)	321-326
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	8
Issue number	3
DOIs	https://doi.org/10.1021/acsmedchemlett.6b00491
State	Published - Mar 9 2017

Keywords

Schiff-base formation
Sickle cell disease
aldehyde
allosteric modulator
oxygen affinity
red blood cell partitioning
sickle cell hemoglobin

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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Metcalf, B., Chuang, C., Dufu, K., Patel, M. P., Silva-Garcia, A., Johnson, C., Lu, Q., Partridge, J. R., Patskovska, L., Patskovsky, Y., Almo, S. C., Jacobson, M. P., Hua, L., Xu, Q., Gwaltney, S. L., Yee, C., Harris, J., Morgan, B. P., James, J., ... Li, Z. (2017). Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Medicinal Chemistry Letters, 8(3), 321-326. https://doi.org/10.1021/acsmedchemlett.6b00491

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. / Metcalf, Brian; Chuang, Chihyuan; Dufu, Kobina; Patel, Mira P.; Silva-Garcia, Abel; Johnson, Carl; Lu, Qing; Partridge, James R.; Patskovska, Larysa; Patskovsky, Yury; Almo, Steven C.; Jacobson, Matthew P.; Hua, Lan; Xu, Qing; Gwaltney, Stephen L.; Yee, Calvin; Harris, Jason; Morgan, Bradley P.; James, Joyce; Xu, Donghong; Hutchaleelaha, Athiwat; Paulvannan, Kumar; Oksenberg, Donna; Li, Zhe.

In: ACS Medicinal Chemistry Letters, Vol. 8, No. 3, 09.03.2017, p. 321-326.

Research output: Contribution to journal › Article

Metcalf, B, Chuang, C, Dufu, K, Patel, MP, Silva-Garcia, A, Johnson, C, Lu, Q, Partridge, JR, Patskovska, L, Patskovsky, Y, Almo, SC, Jacobson, MP, Hua, L, Xu, Q, Gwaltney, SL, Yee, C, Harris, J, Morgan, BP, James, J, Xu, D, Hutchaleelaha, A, Paulvannan, K, Oksenberg, D & Li, Z 2017, 'Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin', ACS Medicinal Chemistry Letters, vol. 8, no. 3, pp. 321-326. https://doi.org/10.1021/acsmedchemlett.6b00491

Metcalf, Brian ; Chuang, Chihyuan ; Dufu, Kobina ; Patel, Mira P. ; Silva-Garcia, Abel ; Johnson, Carl ; Lu, Qing ; Partridge, James R. ; Patskovska, Larysa ; Patskovsky, Yury ; Almo, Steven C. ; Jacobson, Matthew P. ; Hua, Lan ; Xu, Qing ; Gwaltney, Stephen L. ; Yee, Calvin ; Harris, Jason ; Morgan, Bradley P. ; James, Joyce ; Xu, Donghong ; Hutchaleelaha, Athiwat ; Paulvannan, Kumar ; Oksenberg, Donna ; Li, Zhe. / Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. In: ACS Medicinal Chemistry Letters. 2017 ; Vol. 8, No. 3. pp. 321-326.

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abstract = "We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).",

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AU - Oksenberg, Donna

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