title: GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.
abstract: A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease-modifying agent in sickle cell patients.
authors.affiliation: Global Blood Therapeutics Inc., South San Francisco, CA, USA. doksenberg@globalbloodtx.com.
authors.forename: Donna
authors.initials: D
authors.lastname: Oksenberg
authors.affiliation: Global Blood Therapeutics Inc., South San Francisco, CA, USA.
authors.forename: Kobina
authors.initials: K
authors.lastname: Dufu
authors.affiliation: Global Blood Therapeutics Inc., South San Francisco, CA, USA.
authors.forename: Mira P
authors.identifier: 0000-0001-9940-6964
authors.initials: MP
authors.lastname: Patel
authors.affiliation: Cytokinetics, South San Francisco, CA, USA.
authors.forename: Chihyuan
authors.initials: C
authors.lastname: Chuang
authors.affiliation: Global Blood Therapeutics Inc., South San Francisco, CA, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: Global Blood Therapeutics Inc., South San Francisco, CA, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Global Blood Therapeutics Inc., South San Francisco, CA, USA.
authors.forename: Abel
authors.initials: A
authors.lastname: Silva-Garcia
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Chengjing
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Global Blood Therapeutics Inc., South San Francisco, CA, USA.
authors.forename: Athiwat
authors.initials: A
authors.lastname: Hutchaleelaha
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Larysa
authors.initials: L
authors.lastname: Patskovska
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Yury
authors.initials: Y
authors.lastname: Patskovsky
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.affiliation: Global Blood Therapeutics Inc., South San Francisco, CA, USA.
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.affiliation: Global Blood Therapeutics Inc., South San Francisco, CA, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Metcalf
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: David R
authors.identifier: 0000-0002-9185-0865
authors.initials: DR
authors.lastname: Archer
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D000986:Antisickling Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001784:Blood Gas Analysis; D002470:Cell Survival / Q000187:drug effects*; D004195:Disease Models, Animal; D004913:Erythrocytes, Abnormal / Q000187:drug effects* / Q000378:metabolism*; D006451:Hemoglobin, Sickle / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010100:Oxygen / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding
chemical_list: D000986:Antisickling Agents; D006451:Hemoglobin, Sickle; D010100:Oxygen
keywords: haemoglobin; oxygen affinity; pharmacokinetics; sickle cell disease; sickle cell murine model; therapeutic