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 › peer-review

127 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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10.1021/acsmedchemlett.6b00491

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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

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

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

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).",

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

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

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doi = "10.1021/acsmedchemlett.6b00491",

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T1 - Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

AU - Metcalf, Brian

AU - Chuang, Chihyuan

AU - Dufu, Kobina

AU - Patel, Mira P.

AU - Silva-Garcia, Abel

AU - Johnson, Carl

AU - Lu, Qing

AU - Partridge, James R.

AU - Patskovska, Larysa

AU - Patskovsky, Yury

AU - Almo, Steven C.

AU - Jacobson, Matthew P.

AU - Hua, Lan

AU - Xu, Qing

AU - Gwaltney, Stephen L.

AU - Yee, Calvin

AU - Harris, Jason

AU - Morgan, Bradley P.

AU - James, Joyce

AU - Xu, Donghong

AU - Hutchaleelaha, Athiwat

AU - Paulvannan, Kumar

AU - Oksenberg, Donna

AU - Li, Zhe

PY - 2017/3/9

Y1 - 2017/3/9

N2 - 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).

AB - 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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KW - Sickle cell disease

KW - aldehyde

KW - allosteric modulator

KW - oxygen affinity

KW - red blood cell partitioning

KW - sickle cell hemoglobin

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

Abstract

Keywords

ASJC Scopus subject areas

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