The DOI matches its Crossref record; 17 of the 18 references it cites were found in a registry or an index.
Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin
Open accessAbstract
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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“An aldehyde-containing natural product and several synthetic aldehyde analogues were found to prevent polymerization by increasing the affinity of HbS for oxygen143.”
From Advances in covalent drug discovery (2022) · cites this paper as [143]
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Kato, G. J., Piel, F. B., Reid, C. D., Gaston, M. H., Ohene-Frempong, K., Krishnamurti, L., Smith, W. R., Panepinto, J. A., Weatherall, D. J., Costa, F. F., et al. (2018) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2018.10 · Cited by 1,501
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Advances in covalent drug discovery
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Hemoglobin: Structure, Function and Allostery
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Metadata
- 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
- 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)
- 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
- 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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