PROTACs are trimeric small molecules consisting of a specific modulator of the target protein connected to a ligase-recruiting ligand via a suitably flexible linker. Ligase-recruiting ligands deliver ubiquitin ligases like E3 ligase to the Protein of Interest (POI). The vicinity of the POI-PROTAC-E3 ternary complex enables the E3 ligase to ubiquitinate the surface lysine residues of the POI. The Ubiquitin–Proteasome System (UPS) then degrades the POI. However, despite the considerable advances in the design of PROTACs targeting several types of enzymes and receptors, this strategy is still facing the challenges of precision target delivery and duration of action. In this review, we highlight the recent approaches for the development of PROTAC prodrugs or pro-PROTAC to control the delivery of PROTACs and achieve the required on-target exposure. This strategy may facilitate the application of the PROTAC technology and expand its clinical benefits.

Autoimmune diseases (ADs) affect almost 10% of the world population. They are also the leading cause of mortality among young and middle-aged women. Despite the available of therapeutic agents there is no definitive cure. The voltage-gated potassium channel (Kv1.3) plays a key role regulating various physiological processes, particularly immune responses, making it a promising target for immunomodulators. Moreover, the ability of Kv1.3 blockers to selectively modulate the activation of effector memory T-cells, without affecting other lymphoid subsets, make it a promising target to avoid fatal opportunistic infections encountered with broad spectrum immunosuppressants. Herein, a β-carboline-based lead (KMA) was developed through ligand-directed scaffold hopping based on the known Kv1.3 inhibitors, pyranoquinolinone and CP-339,818. Iterative structural derivatization and scaffold hopping produced piperidine and the hybrid analogs based on scaffolds of the potent Kv1.3 small inhibitors, UK-78,282 and PAP-1. Our biological assays produced two promising compounds; β-carboline-based (5c) and hybrid (13a). Notably, the hybrid compound 13a showed promising activity in relation to the Centruroides margaritatus scorpion short-chain toxin, margatoxin, which was used as positive control standard. Only compound 13a managed to decrease the Kv1.3 peak current amplitude by more than 80%, suggesting its viability as a lead compound for further investigations targeting ADs.