@article{5c59b5fab0484427920dafa771398c7e,
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",
note = "Funding Information: The authors thank Dr. Peter Rademacher for running HRMS for selected compounds. We wish to acknowledge the Hemoglobinopathy Center at the Children?s Hospital Oakland Research Institute (CHRCO, Oakland, CA) for providing blood from sickle cell patients. We thank J. Holton, G. Meigs, and ALS staff of beamline 8.3.1 for data collection and helpful discussions. Beamline 8.3.1 at the Advanced Light Source is operated by the University of California Office of the President, Multicampus Research Programs and Initiatives grant MR-15-328599 and Program for Breakthrough Biomedical Research, which is partially funded by the Sandler Foundation. Additional support comes from National Institutes of Health (GM105404, GM073210, GM082250, GM094625), National Science Foundation (1330685), Plexxikon Inc., and the M.D. Anderson Cancer Center. The Advanced Light Source (Berkeley, CA), a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the US Department of Energy under contract number DE-AC02-05CH11231, Office of Basic Energy Sciences, through the Integrated Diffraction Analysis Technologies program, supported by the US Department of Energy Office of Biological and Environmental Research.",
year = "2017",
month = mar,
day = "9",
doi = "10.1021/acsmedchemlett.6b00491",
language = "English (US)",
volume = "8",
pages = "321--326",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",
number = "3",
}