Hydroxypyridinethione Inhibitors of Human Insulin‐Degrading Enzyme

Abstract

Insulin‐degrading enzyme (IDE) is a human mononuclear Zn2+‐dependent metalloenzyme that is widely regarded as the primary peptidase responsible for insulin degradation. Despite its name, IDE is also critically involved in the hydrolysis of several other disparate peptide hormones, including glucagon, amylin, and the amyloid β‐protein. As such, the study of IDE inhibition is highly relevant to deciphering the role of IDE in conditions such as type‐2 diabetes mellitus and Alzheimer disease. There have been few reported IDE inhibitors, and of these, inhibitors that directly target the active‐site Zn2+ ion have yet to be fully explored. In an effort to discover new, zinc‐targeting inhibitors of IDE, a library of ∼350 metal‐binding pharmacophores was screened against IDE, resulting in the identification of 1‐hydroxypyridine‐2‐thione (1,2‐HOPTO) as an effective Zn2+‐binding scaffold. Screening a focused library of HOPTO compounds identified 3‐sulfonamide derivatives of 1,2‐HOPTO as inhibitors of IDE (Ki values of ∼50 μM). Further structure‐activity relationship studies yielded several thiophene‐sulfonamide HOPTO derivatives with good, broad‐spectrum activity against IDE that have the potential to be useful pharmacological tools for future studies of IDE.

Insulin-Degrading Enzyme, an Under-Estimated Potential Target to Treat Cancer?

“…While most inhibitors of IDE are pan-substrate inhibitors ( BDM44768, Ii1 ) [ 62 , 138 ], some are selective for a single substrate [ 139 ] ( 6bK ) or behave as activators for some substrates ( BDM43079 ) [ 140 , 141 ]. These small-organic or peptidic compounds were most often discovered either by the screening of diverse or focused libraries [ 140 , 141 ], DNA-templated libraries ( 6bK) [ 139 ], fragments [ 142 ] or drugs [ 143 ] ( ebselen ) or discovered via a kinetic target-guided synthesis ( BDM44768 ) [ 62 ]. A few inhibitors were designed by rational design, taking inspiration from either insulin ( Ii1 ) [ 138 ] or a VZV peptide (compound ADT21).…”

Insulin-Degrading Enzyme: Paradoxes and Possibilities

“…In my opinion, the field needs to revisit the questions of where in the cell IDE is located, whether it is secreted and, if so, precisely how. Rather than relying exclusively on published reports, most several decades old and some using less-than-ideal methodologies, we should make full use of the powerful new tools now available, such as IDE-null cells [ 6 , 8 ], multiple monoclonal antibodies [ 48 ], and IDE-specific molecular probes [ 9 , 49 , 50 , 51 , 52 ], which should be deployed in tandem with modern labeling and imaging techniques. As for the secretion of IDE, I believe more in vivo studies are needed to verify whether IDE is (ordinarily) present extracellularly and, if so, to what extent.…”

“…Moreover, because substrates make extensive contacts throughout the internal chamber, including at multiple sites distal to the active site, this explains IDE’s otherwise baffling substrate specificity, such as how IDE avidly degrades IGF II, for example, but only slowly degrades similarly sized, related substrates such as IGF I [ 60 , 61 , 62 ]. The extensive and variable contacts made between different substrates and IDE also help explain why small-molecule modulators of IDE frequently show striking substrate-specific differences in potency; indeed, compounds that activate the degradation of some substrates can actually inhibit the degradation of others [ 49 , 63 ]. Most recently, this peculiar property has been quite usefully exploited to develop insulin-specific inhibitors of IDE [ 50 ].…”

“…It needs to be emphasized that until 2010—more than 60 years after the discovery of IDE—there were literally no selective pharmacological inhibitors of IDE or any member of its unusual peptidase superfamily [ 87 ]. Since that time, numerous inhibitors were developed that are: (1) potent and selective for IDE [ 9 , 11 , 50 , 51 , 87 , 88 , 89 ]; (2) in vivo compatible [ 11 , 52 , 89 ]; (3) selective for extracellular IDE exclusively [ 52 , 90 ]; (4) inexpensive to synthesize [ 49 , 51 ]; and (5) substrate selective [ 88 , 91 , 92 ], with many compounds with multiple meritorious properties simultaneously. These IDE inhibitors represent a powerful yet essentially untapped resource for the field, which could be used to address numerous topics.…”

Identification of Electrostatic Hotspots at the Binding Interface of Amylin and InsulinDegrading Enzyme: A Structural and Biophysical Investigation

“…Amylin is a 37-amino-acid pancreatic hormone acting to control energy homeostasis and body weight [1][2][3][4]. Physiologically, amylin regulates glucose homeostasis by inhibiting insulin and glucagon secretion [5][6][7]. Furthermore, amylin modulates satiety and inhibits gastric emptying via the central nervous system [8][9][10][11].…”