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

Brian Metcalf, Chihyuan Chuang, Kobina Dufu, Mira P. Patel, Abel Silva-Garcia, Carl Johnson, Qing Lu, James R. Partridge, Larysa Patskovska, Yury Patskovsky, Steven C. Almo, Matthew P. Jacobson, Lan Hua, Qing Xu, Stephen L. Gwaltney, Calvin Yee, Jason Harris, Bradley P. Morgan, Joyce James, Donghong XuAthiwat Hutchaleelaha, Kumar Paulvannan, Donna Oksenberg, Zhe Li

Research output: Contribution to journalArticlepeer-review

123 Scopus citations


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 languageEnglish (US)
Pages (from-to)321-326
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number3
StatePublished - Mar 9 2017


  • Schiff-base formation
  • Sickle cell disease
  • aldehyde
  • allosteric modulator
  • oxygen affinity
  • red blood cell partitioning
  • sickle cell hemoglobin

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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