Cited by 208Hemoglobinopathies and Related DisordersHemoglobin structure and functionErythrocyte Function and Pathophysiology

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

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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·2017·ACS Medicinal Chemistry Letters

DOI 10.1021/acsmedchemlett.6b00491PMC PMC5346980

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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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Authors: 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., Xu, D., Hutchaleelaha, A., Paulvannan, K., Oksenberg, D., & Li, Z.
Affiliations: Global Blood Therapeutics (United States) (US)
Cytokinetics, Inc. , , ,
Global Blood Therapeutics, Inc. , , ,
Albert Einstein College of Medicine (US)
University of California, San Francisco (US)
Cytokinetics (United States) (US)
Tandem Sciences, Inc. , , ,
Corresponding author: Li, Zhe
ORCID: Metcalf, Brian
Dufu, Kobina
Patel, Mira P.
Partridge, James R.
Patskovsky, Yury
Almo, Steven C.
Jacobson, Matthew P.
Xu, Qing
Gwaltney, Stephen L.
Morgan, Bradley P.
Xu, Donghong
Hutchaleelaha, Athiwat
Li, Zhe
Venue: ACS Medicinal Chemistry Letters
Publisher: American Chemical Society (ACS)
Published: 2017-01-23
Volume: 8
Issue: 3
Pages: 321-326
ISSN: 1948-5875 (ISSN-L)
DOI: 10.1021/acsmedchemlett.6b00491
PMC: PMC5346980
OpenAlex: W2580609256
Semantic Scholar: 4e07fd4fe03da372d946bd5c9a5a2b11260c7128
Cited by: 203
References: 18
Citations by year: 2026: 15 · 2025: 31 · 2024: 26 · 2023: 25 · 2022: 29 · 2021: 19 · 2020: 23 · 2019: 17 · 2018: 15 · 2017: 3
FWCI: 8.94
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: other-oa
pubs.acs.org/page/policy/authorchoice_termsofuse.html (vor, 19 d)
Locations: ACS Medicinal Chemistry Letters (publishedVersion, other-oa)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Institute of General Medical Sciences (GM073210, GM082250, GM094625, GM105404)
National Science Foundation (1330685)
University of Texas MD Anderson Cancer Center
Plexxikon Inc.
Topics: Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
Health Sciences › Medicine › Physiology (medical) › Erythrocyte Function and Pathophysiology
Keywords: hemoglobin S, allosteric effectors, oxygen affinity, hypoxia, oral bioavailability, sickle cell disease, drug discovery

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

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