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 | |
| State | Published - Mar 9 2017 |
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Keywords
- aldehyde
- allosteric modulator
- oxygen affinity
- red blood cell partitioning
- Schiff-base formation
- Sickle cell disease
- sickle cell hemoglobin
ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Organic Chemistry
Cite this
Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. / 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.
In: ACS Medicinal Chemistry Letters, Vol. 8, No. 3, 09.03.2017, p. 321-326.Research output: Contribution to journal › Article
}
TY - JOUR
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).
KW - aldehyde
KW - allosteric modulator
KW - oxygen affinity
KW - red blood cell partitioning
KW - Schiff-base formation
KW - Sickle cell disease
KW - sickle cell hemoglobin
UR - http://www.scopus.com/inward/record.url?scp=85014916782&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014916782&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.6b00491
DO - 10.1021/acsmedchemlett.6b00491
M3 - Article
AN - SCOPUS:85014916782
VL - 8
SP - 321
EP - 326
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 3
ER -