Themed collection Induced-Proximity Pharmacology

PROTACs are an emerging therapeutic approach towards targeted protein degradation. This article examines the leading examples of this modality that are in clinical development through the prism of their physicochemical properties.

Ligand-directed site-specific covalent modification of protein surfaces will advance synthetic re-wiring of biological pathways.

Degrons are regions of a protein that are required to initiate their degradation by cellular machinery.

ER PROTACs emerge as a hopeful and innovative strategy for combating endocrine-resistant breast cancer.

As the field of targeted protein degradation has advanced, it has expanded beyond traditional recruitment to E3 substrate receptors to new approaches involving recruitment to a variety of other components within the ubiquitin proteasome system.

A comprehensive outlook of PROTAC breakthroughs in targeting anti-inflammatory and auto-immune diseases as promising therapeutic approaches for various unresolved disorders.

Niclosamide, an FDA-approved anthelmintic drug, known to uncouple the mitochondria induces cyclin D1 degradation via CRL4^AMBRA1. We find a striking correlation between the two processes and that it is observed amongst various compounds.

Chimeric small molecule LH-3, designed to recruit the VHL E3 ligase, degrades HBV protein HBeAg through a largely VHL-independent mechanism. Virological assessment reveals enhanced efficacy against an inhibitor-resistant strain of the virus.

This study suggests a tailored in vitro DMPK discovery assay cascade and frontloading in vivo studies. It also underlines the need for inclusion of surrogate permeability descriptors and experimentally determined values for IVIVE of CL_int.

Strong ligand directed degraders stabilize the hydrophobic residue burial between the E3 ligase and the target protein to be degraded. Weak degraders destabilize the ternary complex through multiple mechanisms.

The first degrader of an ER-resident protein (IRE1α) is described with properties more akin to a molecular glue than a traditional PROTAC, thus challenging the dogma of categorizing degrader modalities based on their physicochemical features.

The first light-activatable photochemically targeting chimeras (PHOTACs) designed for the targeted degradation of histone deacetylase 6 are reported.

High-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis and biological evaluation of crude mixtures in cellular assays.

p300 and CBP are paralogous epigenetic regulators and promising therapeutic targets for which TPD offers the potential to achieve paralog-selective degradation.

The unique molecular topologies of the two different binding sites of the Tau/14-3-3 protein–protein interaction were exploited to develop selective dynamic covalent molecular glues for the Tau pS214 site.

Disclosure of composite efficiency scores for protein degraders that account for potency and depth of degradation.

Application of copper-catalyzed azide–alkyne cycloaddition (CuAAC) “click” reactions assemble bivalent proteolysis-targeting chimeras (PROTACs) constituents targeting tyrosyl-DNA phosphodiesterase 1 (TDP1).

An HTRF assay was developed to measure the DCAF16–SPIN4 interaction and was subsequently employed to screen for DCAF16 recruiters. A hit compound, 2G07, was identified and further optimized into a PROTAC for the targeted degradation of FKBP12.

A novel hydrophobic cell-penetrating peptide (CPP) and heteroduplex oligonucleotide (HDO)-conjugated PROTAC, CPP/HDO-PROTAC, was designed to enhance its intracellular delivery and degradation efficiency.

We designed and synthesized novel IOX1-based PROTACs, which can selectively degrade KDM3A and KDM3B to eliminate colorectal cancer stem cells through inhibition of Wnt signaling.

The interaction of PD-L1 and PD-1 transmits the inhibitory signal to reduce the proliferation of antigen-specific T-cells in lymph nodes.

Discovery of the first-in-class PROTACs targeting maternal embryonic leucine zipper kinase (MELK) for the treatment of Burkitt lymphoma.