Table 1. Examples of the major drug classes producing a positive insulin resistance-drug repurposing (IR-DR) score and associated literature evidencing efficacy.
In vivo refers to evidence for in vivo validation of the drug and/or its target proteins.
| Pathway | Example drug | Biology narrative | In vivo | Example literature |
|---|---|---|---|---|
| ATPase/cardiac glycoside | Proscillaridin, digoxin | Heart failure drug; possibly mimicking the action of metformin on mitochondria in vitro; senolytic. | No | Fürstenwerth, 2012; Triana-Martínez et al., 2019 |
| Calcium channel | Nifedipine | Restores autophagy, improves glucose tolerance and insulin action. | Yes | Iwai et al., 2011; Koyama et al., 2002; Lee et al., 2019; Sheu et al., 1991 |
| Calcium/calmodulin signalling | NM-PP1 | Insulin signalling upstream of p38; restores ATF6-related autophagy; insulin resistance, diabetes and Alzheimer’s pathophysiology. | Yes | Alfazema et al., 2019; Ozcan et al., 2015; Ozcan et al., 2013; Yin et al., 2017 |
| Dopamine | L-741626 | Central and peripheral role in regulation of glucose tolerance – contradictory/paradoxical behavioural/hepatic agonist/antagonist activity. | Yes | Amamoto et al., 2006; Fontaine et al., 2020; Kellar and Craft, 2020; Park et al., 2007; Stoelzel et al., 2020 |
| Tyrosine kinase/ERBB receptor inhibitors | Canertinib, gefitinib, afatinib | Inhibition of EGFR, DDR1, ABL1 and related kinases produces a positive IR-DR score. Extensive data link EGFR and inhibitors of EGFR to insulin resistance and neurodegeneration. Pro-inflammatory signalling via iRHOM2 and MAP3K7; circulating biomarker of insulin resistance and hepatic metabolic disease. | Yes | Chen et al., 2019; Chiu et al., 2020; Fowler et al., 2020; Kyohara et al., 2020; Li et al., 2018b; Skurski et al., 2020; Vella et al., 2019; Wang et al., 2012; Wu et al., 2017 |
| Glucocorticoid/anti-inflammatory | Valdecoxib, Spectrum_001832 | Anti-inflammatory; various steroidal and non-steroidal anti-inflammatory drugs reduce IR in a variety of models of diabetes/obesity. Excess corticosteroids induce IR. | Yes | Chakraborti et al., 2010; Chan et al., 2018; Reading et al., 2013 |
| Glucosylceramide synthase | BRD-K88761633, AMP-DNM | Glycosphingolipid biosynthesis – inhibition treats insulin resistance and fatty liver disease. | Yes | Aerts et al., 2007; Herrera Moro Chao et al., 2019 |
| Heat-shock protein 90 | Luminespib | ATPase cycle and chaperone function – inhibition improves insulin sensitivity; Hsp90 activated in dementia. Role in INSR turnover and protein phosphatase 5 activation. | Yes | Imamura et al., 1998; Jing et al., 2018; Shelton et al., 2017; Yang et al., 2005 |
| MAPK/MEK/ERK inhibitors | PD-184352, PD-0325901, XMD-892 | Multiple roles in insulin signalling and metabolism; inhibitors target multiple kinases. | Yes | Ozaki et al., 2016; Sharma et al., 2014; Tarragó et al., 2018; Wauson et al., 2013 |
| mTOR related | AZD-8055, WYE-354, torin-2 | Inhibition of mTORC1 activity – including knock-down of RAPTOR – produces a strong positive IR-DR score. In multiple studies, mTOR inhibition reduces age-related metabolic dysfunction. | Yes | Howell et al., 2017; Jahng et al., 2019; Morita et al., 2013; Nie et al., 2018a; Norambuena et al., 2017; Zhan et al., 2019 |
| Nicotinamide phosphoribosyltransferase | CAY-10618 (GPP78) | NAMPT (or visfatin) inhibitor which attenuates atherosclerosis in the high-fat-induced insulin resistance model and is anti-inflammatory. | Yes | Li et al., 2016; Lockman et al., 2010; Travelli et al., 2017 |
| Phosphodiesterase 5A | MBCQ, sidenafil | PDE5A is negative regulator of insulin, aspects of ageing – potentially via miR-22-3p. | Yes | Blagosklonny, 2017; Fiore et al., 2018; Fiore et al., 2016; Liu et al., 2019 |
| Phosphoinositide 3-kinase | AZD-6482, PI-103, GDC-0941 | Multiple PI3K inhibitors produce strong positive IR-DR scores. In multiple studies PI3K varies with metabolic dysfunction; however, all kinase inhibitors target multiple related kinases, so specific target unclear. | No | Chiu et al., 2020; Copps et al., 2016; Wang et al., 2020; Zou et al., 2004 |
| RAF kinase | AZ-628, vemurafenib | RAF1 is increased in obesity-induced IR, inhibitors can block insulin/AKT1/MAPK signalling in a context-specific manner. AZ-628 also RIP3 inhibitor – anti-arthritis strategy. | No | MacLaren et al., 2008; Osrodek et al., 2020; Sun et al., 2016 |
EGFR, epidermal growth factor receptor.