PROTACs– a game-changing technology

Abstract

Introduction: Proteolysistargeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules comprising of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a connecting linker. The aim is instead of inhibiting the target to induce its proteasomal degradation. Areas covered: PROTACs, due to their bifunctional design, possess properties that differentiate them from classical inhibitors. A structural analysis, based on published crystal aspects, kinetic features and aspects of selectivity are discussed. Specific types such as homoPROTACs, PROTACs targeting Tau protein and the first PROTACs recently entering clinical trials are examined. Expert opinion: PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders. Moreover, PROTACs are standing out from classical pharmacology by inducing the degradation of the target protein and not merely its inhibition. However, there are also challenges in the field, such as the rational structure optimization, the evolution of computational tools, limited structural data and the greatly anticipated clinical data. Despite the remaining hurdles, PROTACs are expected to soon become a new therapeutic category of drugs.

Covalent inhibitors: a rational approach to drug discovery

“…PROTACs are an exciting new modality of heterobifunctional molecules aiming to degrade the protein of interest instead of inhibiting it. 25 , 26 In 2019, Gray et al 27 reported the development of a cereblon-based degrader molecule library targeting KRASG12C and bearing acrylamide warheads. Although the lead PROTAC ( Fig.…”

Acetylcholinesterase: The “Hub” for Neurodegenerative Diseases and Chemical Weapons Convention

“…Galantamine acts simultaneously as an AChE inhibitor and allosteric modulator of nicotinic receptors, increasing the affinity for ACh [114][115][116][117][118][119][120][121][122][123][124][125][126][127][128]. Research in progress on novel AD drugs has covered different disciplines and been focused on further development of AChE inhibitors, beta-secretase 1 (BACE-1) inhibitors, serotonin 5-HT4 receptor inhibitors and PROTAC (PROteolysis Targeting Chimeras) compounds, among other approaches [129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146]. Rivastigmine is regarded to react with the serine residue of the ES present in AChE and BChE (as shown in Scheme 3), whereas donepezil can act in both CAS and PAS of AChE.…”

Automated, Accelerated Nanoscale Synthesis of Iminopyrrolidines

“…As part of our ongoing interest in proteolysis targeting chimeras (PROTACs), we aimed to produce libraries centered around the glutarimide pharmacophore addressing the E3 ligase Cereblon using multicomponent reactions (MCR) . For this, we went back to a report of the use of glutamine (Gln) in the Ugi reaction (U‐5C‐4CR), yielding highly substituted glutarimide derivatives (Figure A) .…”