Zielgerichtete kovalente Inhibitoren für das Wirkstoffdesign

Abstract

Abweichend vom üblichen Arzneimittelwirkmechanismus einer reversiblen, nichtkovalenten Wechselwirkung eines Liganden mit seinem biologischen Zielmolekül wird ein zielgerichteter kovalenter Inhibitor (TCI) so entwickelt, dass nach einer anfänglichen reversiblen Assoziation eine kovalente Bindung zwischen einem Elektrophil auf dem Liganden und einem nucleophilen Zentrum auf dem Protein geknüpft wird. Obwohl diese Methode einige potenzielle Vorteile bietet (hohe Wirksamkeit, verlängerte Wirkung), haben Bedenken wegen möglicher toxikologischer Folgen durch Proteinhaptenisierung die Entwicklung des TCI‐Konzepts aufgehalten. Neue Ansätze zur Verringerung des Risikos ernster ungünstiger Reaktionen regten das Interesse an diesem Gebiet an und führten zur Vertriebsgenehmigung für eine erste Serie von TCIs. Der Zugang über kovalente Inhibitoren wird daher rasch als nützliches Mittel in der Arzneimittelforschung akzeptiert werden und großen Einfluss auf das Design von Enzyminhibitoren und Rezeptormodulatoren ausüben.

A Triazolotriazine‐Based Dual GSK‐3β/CK‐1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition

“…The main pathological hallmarks of PD are the loss of dopaminergic neurons and the presence of eosinophilic inclusions, called Lewy bodies (LB), in the substantia nigra parsc ompacta of the midbrain. In recent years, there has been ar esurgence of interest in covalent inhibitors, [11] and the 2-cyanoacrylamide group can [a] Dr. In recent years, many researchers have reported that GSK-3b is implicated in microglial-mediated inflammation.…”

“…In recent years, many researchers have reported that GSK-3b is implicated in microglial-mediated inflammation. In recent years, there has been ar esurgence of interest in covalent inhibitors, [11] and the 2-cyanoacrylamide group can [a] Dr. [3] Furthermore, GSK-3b and CK-1d are responsible for the phosphorylation of proteins that are abundant in the LB, including tau, a-synuclein, and parkin.…”

“…[8,9] GSK-3b inhibition was displayed by the 5,7-dicyclohexylamino derivative 4 [IC 50 (GSK-3b) = 5.02 mm]( Ta ble1). In recent years, there has been ar esurgence of interest in covalent inhibitors, [11] give ar eversible thia-Michael reaction, minimizing the chance of irreversible modifications of off-targetp eptides. We therefore introduced the 3-amidophenyl moiety at the 2positiono ft he TT scaffold.…”

“…We hypothesized as imilarp ose betweenA TP and TT in the bindingp ocket of GSK-3b.W et herefore wondered if af ocused substitution at the 2-position of the TT would target the noncatalytic cysteine1 99 (Cys199), leadingt oc ovalent inhibition of GSK-3b,a nd thus to improved potency toward the target. In recent years, there has been ar esurgence of interest in covalent inhibitors, [11] give ar eversible thia-Michael reaction, minimizing the chance of irreversible modifications of off-targetp eptides. [12] For these reasons, we designed the 3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamided erivative (12)w ith an amido moiety to confer potencyt oward CK-1d.…”

Distinguishing the optimal binding mechanism of an E3 ubiquitin ligase: Covalent versus noncovalent inhibition

“…It has been found, that under certain conditions, the properties of covalent drugs could prove beneficial when compared with their noncovalent equivalents. 8 For instance, due to the longlasting effects of a covalent drug, it is able to inhibit the same biological target at a lower concentration than a noncovalent drug. 9,10 An example of this covalent reaction (Michael addition) between a ligand, subject of this study, and its protein target is shown in Figure 1.…”