Large-Scale Drug Screen Identifies FDA-Approved Drugs for Repurposing in Sickle-Cell Disease.

Autor: Cannon M; Division of Hematology, The Ohio State University, Columbus, OH 43210, USA., Phillips H; Division of Hematology, The Ohio State University, Columbus, OH 43210, USA., Smith S; Division of Hematology, The Ohio State University, Columbus, OH 43210, USA., Williams K; Division of Hematology, The Ohio State University, Columbus, OH 43210, USA., Brinton L; Division of Hematology, The Ohio State University, Columbus, OH 43210, USA., Gregory C; Division of Hematology, The Ohio State University, Columbus, OH 43210, USA., Landes K; Division of Hematology, The Ohio State University, Columbus, OH 43210, USA., Desai P; Division of Hematology, The Ohio State University, Columbus, OH 43210, USA., Byrd J; Division of Hematology, The Ohio State University, Columbus, OH 43210, USA.; College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.; Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA., Lapalombella R; Division of Hematology, The Ohio State University, Columbus, OH 43210, USA.
Jazyk: angličtina
Zdroj: Journal of clinical medicine [J Clin Med] 2020 Jul 17; Vol. 9 (7). Date of Electronic Publication: 2020 Jul 17.
DOI: 10.3390/jcm9072276
Abstrakt: Sickle-cell disease (SCD) is a debilitating hematological disorder with very few approved treatment options. Therapeutic reactivation of fetal hemoglobin (HbF) is one of the most pursued methods for ameliorating the systemic manifestations of SCD. Despite this, very few pharmacological agents have advanced to clinical trials or marketing for use. In this study, we report the development of an HbF in situ intracellular immunoblot assay coupled to a high-throughput drug screen to identify Food and Drug Administration (FDA) approved drugs that can be repurposed clinically for treatment of SCD. Using this assay we evaluated the National Institute of Health (NIH) Clinical Collection (NCC), a publicly available library of 725 small molecules, and found nine candidates that can significantly re-express HbF in erythroid cell lines as well as primary erythroblasts derived from SCD patients. Furthermore, we show the strong effects on HbF expression of these candidates to occur with minimal cytotoxicity in 7 of the 9 drugs. Given these data and their proven history of use for other indications, we hypothesize that several of these candidate drugs warrant further investigation for use in SCD.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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