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

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.

Targeting human thymidylate synthase: Ensemble-based virtual screening for drug repositioning and the role of water

“…The pharmacokinetic pro le such as its oral bioavailability at 98%, and its tolerability make Imatinib an attractive candidate to reposition. It is therefore, not surprising that Imatinib has been studied for drug repositioning for several therapeutic targets and diseases [96][97][98][99][100][101][102][103][104]. In addition, due to its ability to cross the blood brain barrier, Imatinib presented an excellent choice of an approved drug to repurpose for neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) [105].…”

A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs

“…Alternatively, a growing evidence support the concept that induction of fetal hemoglobin (HbF) by pharmacological agents might be of great interest for the development of therapeutic protocols for β-thalassemia [18][19][20] . Induction of HbF has been the object of several studies and review papers [21][22][23] and at this stage there are several compounds that reached the stage of clinical testing, including sirolimus (see later), benserazide and thalidomide 20,24 .…”

In Humanized Sickle Cell Mice, Imatinib Protects Against Sickle Cell–Related Injury

“…In rare diseases, drug repurposing, which explores known and unexpected effects of molecules already in clinical use for treatment of other disorders is a valuable strategy. [1][2][3] Different approaches might be put in place to select candidate molecules to be re-purposed. Among them, an experimental data-driven strategy might be extremely interesting in the context of rare diseases.…”

“…Among them, an experimental data-driven strategy might be extremely interesting in the context of rare diseases. 1–3…”