Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin.
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,36binds with a 1:1 stoichiometry. Compound36is 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).
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Brian
B
Metcalf
Cytokinetics, Inc. , South San Francisco, California 94080, United States.
Chihyuan
C
Chuang
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Kobina
K
Dufu
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Mira P
MP
Patel
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Abel
A
Silva-Garcia
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Carl
C
Johnson
Cytokinetics, Inc. , South San Francisco, California 94080, United States.
Qing
Q
Lu
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
James R
JR
Partridge
Albert Einstein College of Medicine , Bronx, New York 10461, United States.
Larysa
L
Patskovska
Albert Einstein College of Medicine , Bronx, New York 10461, United States.
Yury
Y
Patskovsky
Albert Einstein College of Medicine , Bronx, New York 10461, United States.
Steven C
SC
Almo
Department of Pharmaceutical Chemistry, University of California , San Francisco, California 94158, United States.
Matthew P
MP
Jacobson
Department of Pharmaceutical Chemistry, University of California , San Francisco, California 94158, United States.
Lan
L
Hua
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Qing
Q
Xu
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Stephen L
SL
Gwaltney
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Calvin
C
Yee
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Jason
J
Harris
Cytokinetics, Inc. , South San Francisco, California 94080, United States.
Bradley P
BP
Morgan
Cytokinetics, Inc. , South San Francisco, California 94080, United States.
Joyce
J
James
Cytokinetics, Inc. , South San Francisco, California 94080, United States.
Donghong
D
Xu
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Athiwat
A
Hutchaleelaha
Tandem Sciences, Inc. , Menlo Park, California 94025, United States.
Kumar
K
Paulvannan
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Donna
D
Oksenberg
Global Blood Therapeutics, Inc. , South San Francisco, California 94080, United States.
Zhe
Z
Li
Schiff-base formation; Sickle cell disease; aldehyde; allosteric modulator; oxygen affinity; red blood cell partitioning; sickle cell hemoglobin