N-Heterocycle based Degraders (PROTACs) Manifesting Anticancer Efficacy: Recent Advances

Abstract

Proteolysis Targeting Chimeras (PROTACs) technology has emerged as a promising strategy for the treatment of undruggable therapeutic targets. Researchers have invested a great effort in developing druggable PROTACs; however, the problems associated with PROTACs, including poor solubility, metabolic stability, cell permeability, and pharmacokinetic profile, restrict their clinical utility. Thus, there is a pressing need to expand the size of the armory of PROTACs which will escalate the chances of pinpointing new PROTACs with optimum pharmacokinetic and pharmacodynamics properties. N- heterocycle is a class of organic frameworks that have been widely explored to construct new and novel PROTACs. This review provides an overview of recent efforts of medicinal chemists to develop N-heterocycle-based PROTACs as effective cancer therapeutics. Specifically, the recent endeavors centred on the discovery of PROTACs have been delved into various classes based on the E3 ligase they target (MDM2, IAP, CRBN, and other E3 ligases). Mechanistic insights revealed during the biological assessment of recently furnished Nheterocyclic-based PROTACs constructed via the utilization of ligands for various E3 ligases have been discussed.

Synthesis of a new series of 4-pyrazolylquinolinones with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors

“…21 Heterocycle-based therapies can potentially influence various metabolic pathways and cellular processes in cancer etiology. 22,23 Because of their ability to engage in various intermolecular interactions, including hydrogen bond donor/acceptor capabilities, pi stacking interactions, metal coordination bonds, and van der Waals and hydrophobic forces, they can bind to diverse enzymes in various ways. 24 Because of their different ring sizes and structural permutations, they can fit into the structurally diverse variety of enzyme binding pockets.…”