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

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

Journal of clinical medicine (2020-07-28)
Matthew Cannon, Hannah Phillips, Sidney Smith, Katie Williams, Lindsey Brinton, Charles Gregory, Kristina Landes, Payal Desai, John Byrd, Rosa Lapalombella
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phenazine methosulfate, ≥90% (UV)
Sigma-Aldrich
Triton X-100, laboratory grade
Sigma-Aldrich
Erythropoietin human, EPO, recombinant, expressed in HEK 293 cells, suitable for cell culture
Sigma-Aldrich
Stem Cell Factor human, SCF, recombinant, expressed in HEK 293 cells, suitable for cell culture
Sigma-Aldrich
Phenylmethanesulfonyl fluoride, ≥98.5% (GC)
Sigma-Aldrich
Phosphatase Inhibitor Cocktail 1, DMSO solution
Sigma-Aldrich
Phosphatase Inhibitor Cocktail 2, aqueous solution (dark coloration may develop upon storage, which does not affect the activity)
Sigma-Aldrich
Interleukin-3 human, IL-3, recombinant, expressed in HEK 293 cells, HumanKine®, suitable for cell culture