Gupta 2020). There are usually two strategies involved in DR—on-target and

off-target. The pharmacological mechanism is known in an on-target profile,

whereby the same target is used for a different disease. In contrast, the target is

completely new in an off-target profile. Table 5.1 describes FDA-approved drugs

that have been successfully repositioned classified according to these two strategies.

There are many approaches taken towards DR, especially with the boom of technol-

ogy in the past decade, with the two majors being experiment-based and in silico

approach (Rudrapal et al. 2020).

5.2.1

Experimental Approaches

DR through an experiment-based approach is dependent on experimental assays.

Experimental methods used to identify target interactions are binding assays (affinity

chromatography and mass spectrometry) and phenotypic screenings (high-

throughput screening using in vitro or in vivo models) (Pushpakom et al. 2018). A

group of investigators used an in vitro screening method with US Food and Drug

Administration (FDA)-approved drugs and discovered that ceftriaxone and harmine

can upregulate transported GLT-1, a previously unknown effect (Rothstein et al.

2005). This implication is significant to the development of amyotrophic lateral

sclerosis (ALS). Although the clinical trials of ceftriaxone were eventually halted in

2012, this method was shown to rapidly advance a drug into a clinical testing phase.

In vivo models such as zebrafish models are also used for DR studies. In a study by

Cousin et al., a larval zebrafish model was used to screen 39 FDA-approved drugs

for tobacco dependence and found that 8 drugs from 5 different classes can modify

nicotine behavior (Cousin et al. 2014).

A key player in phenotypic screening is a platform known as theraTRACE^®

developed by Melior Discovery that utilizes 40 mouse disease models in the areas of

inflammation, metabolic disease, immunology, allergic reaction, regenerative, psy-

chotherapeutic, neurology, neurodegenerative disease, pain, gastrointestinal, cardio-

vascular, and urogenital (Cavalla 2013). From this platform, a compound called

MLR-1023, also previously known as tolmidone, discovered by Pfizer was identified

as a candidate for type 2 diabetes through insulin sensitization (Saporito et al. 2012).

This drug was initially developed for gastric ulcer but was discontinued as it was not

efficacious. Another drug, gefitinib, which is an epidermal growth factor receptor

(EGFR) inhibitor, commonly prescribed to lung and breast cancer patients was

studied using affinity chromatography and mass spectrometry. Through this study,

more than 20 different protein kinases and other cellular proteins that are unrelated to

EGFR inhibition were identified (Godl et al. 2005). High-throughput screening using

micropillar arrays (BIMA) to screen for compounds that promote remyelination

discovered that the drug clemastine, widely used for its antihistamine properties,

was a likely candidate for human remyelination trials (Mei et al. 2014). Additionally,

the drug did undergo clinical trial (NCT02040298) as a treatment for patients with

multiple sclerosis (MS), and findings suggested that the drug was safe and myelin

repair could be achieved (ClinicalTrials.gov 2021; Green et al. 2017).

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