Proteolysis Targeting Chimeric Molecules: Tuning Molecular Strategies for a Clinically Sound Listening

Abstract

From seminal evidence in the early 2000s, the opportunity to drive the specific knockdown of a protein of interest (POI) through pharmacological entities called Proteolysis Targeting Chimeric molecules, or PROTACs, has become a possible therapeutic option with the involvement of these compounds in clinical trials for cancers and autoimmune diseases. The fulcrum of PROTACs pharmacodynamics is to favor the juxtaposition between an E3 ligase activity and the POI, followed by the ubiquitination of the latter and its degradation by the proteasome system. In the face of an apparently modular design of these drugs, being constituted by an E3 ligase binding moiety and a POI-binding moiety connected by a linker, the final structure of an efficient PROTAC degradation enhancer often goes beyond the molecular descriptors known to influence the biological activity, specificity, and pharmacokinetics, requiring a rational improvement through appropriate molecular strategies. Starting from the description of the basic principles underlying the activity of the PROTACs to the evaluation of the strategies for the improvement of pharmacodynamics and pharmacokinetics and rational design, this review examines the molecular elements that have been shown to be effective in allowing the evolution of these compounds from interesting proof of concepts to potential aids of clinical interest.

Drugging Protein Tyrosine Phosphatases through Targeted Protein Degradation

“…On the other hand, the discovery and leverage of non‐inhibitory binders of PTPs for degrader development presents a new direction, given that they often provide starting points with preferable specificity and druglike properties. While several PROTAC drugs have progressed to clinical trials, [55] the clinical translation of PROTAC degraders faces the challenge of limited bioavailability due to their relatively high molecular weight and the presence of multiple hydrogen bond donors and acceptors. To address this issue, structure‐based modification of the effective PTP PROTACs for optimal drug‐like properties might be necessary.…”

Proteolysis-Targeting Chimera (PROTAC) Delivery into the Brain across the Blood-Brain Barrier

“…A number of PROTACs have been developed. Clinical trials using PROTACs have been performed only for the treatment of cancers but, however, have not been performed for CNS diseases yet [ 25 , 26 ]. In general, the difficulty of CNS drug development is due to the impermeability of the BBB and wrong distribution.…”

Anticancer Small-Molecule Agents Targeting Eukaryotic Elongation Factor 1A: State of the Art

“…Whereas further details await elucidation, it was believed that metarrestin interferes with certain non-translational functions of eEF1A2. Recently, Jin et al developed a proteolysis-targeting chimera (PROTAC) [ 105 , 106 , 107 ] strategy by tethering metarrestin with various ligands for the von Hippel–Lindau (VHL) E3 ligase [ 108 ]. Thus obtained heterobifunctional molecules were designed to recruit eEF1A2, the binding target of metarrestin, to the ubiquitin/proteasome system (UPS) for selective degradation.…”