Proteolysis-Targeting Chimera (PROTAC): Is the Technology Looking at the Treatment of Brain Tumors?

Severini, Ludovica Lospinoso; Bufalieri, Francesca; Infante, Paola

doi:10.3389/fcell.2022.854352

Cited by 11 publications

(7 citation statements)

References 123 publications

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“…Passage of drugs across the blood-brain barrier is highly dependent on a drug's physicochemical properties, passive diffusion, and uptake and efflux transporters (Di et al 2013). Due to their ability to target proteins that are largely undruggable, TPDs may have significant potential in the treatment of CNS disorders but a number of limitations must be overcome before they can be considered a viable option for CNS disorders (Farrell and Jarome 2021); (Lospinoso Severini et al 2022). Achieving pharmacologically relevant brain or central nervous system concentrations of TPDs presents a significant challenge due to their physicochemical properties.…”

Section: Brain Penetration Potential Of Targeted Protein Degradersmentioning

confidence: 99%

Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders

et al. 2023

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AB-MPS, simple multiparametric scoring function predicting oral absorption, ADME, absorption, distribution, metabolism, and excretion; BCS, biopharmaceutical classification system; BLQ, below the limit of quantification; bRo5, beyond the Lipinski's rule of 5; CNS, central nervous system; CRBN, cereblon E3 ligase; DC 50 , concentration with 50% target degradation; DDI, drug-drug interaction; D max , maximal degradation; DMPK, drug metabolism and pharmacokinetics; EPSA, experimentally determined exposed polar surface area; FaSSIF, fasted simulated intestinal fluid; FeSSIF, fed simulated intestinal fluid; GLP, good laboratory practice; IND, investigational new drug; IV, intravenous administration; HBA, number of hydrogen bond acceptors; HBD, number of hydrogen bond donors; MW, molecular weight; NRB, number of rotatable bonds; PBPK, physiological based pharmacokinetic modeling; PK, pharmacokinetics; PD, pharmacodynamics; PO, oral administration; POI, protein of interest; PPB, plasma protein binding; tPSA, topological polar surface area; RED, rapid equilibrium dialysis; SC, subcutaneous administration; SGF, simulated gastric fluid; TPD, targeted protein degraders specifically PROTACs; VHL, von Hippel-Lindau E3 ligase

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Section: Brain Penetration Potential Of Targeted Protein Degradersmentioning

confidence: 99%

Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders

et al. 2023

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“…( 20, 27 ) U87 cells were also used as this cell line has previously been reported in the development of BRD4 degraders and would be a good model for us to compare our Rpn-13 dependent method. ( 41–43 ) TEC3 and -4 were shown to be able to degrade BRD4 in U87 cells and Raji B-cells ( Figure 3A and 3B ). TEC9 had the same result that was observed in the Ramos B-cells, where BRD4 degradation did not occur.…”

Section: Resultsmentioning

confidence: 98%

ByeTAC: Bypassing an E3 Ligase for Targeted Protein Degradation

Ali,

Loy,

Trader

2024

Preprint

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Targeted protein degradation utilizing a bifunctional molecule to initiate ubiquitination and subsequent degradation by the 26S proteasome has been shown to be a powerful therapeutic intervention. Many bifunctional molecules, including covalent and non-covalent ligands to proteins of interest, have been developed. The traditional target protein degradation methodology targets the protein of interest in both healthy and diseased cell populations, and a therapeutic window is obtained based on the overexpression of the targeted protein. We report here a series of bifunctional degraders that do not rely on interacting with an E3 ligase, but rather a 26S proteasome subunit, which we have named ByeTACs: Bypassing E3 Targeting Chimeras. Rpn-13 is a non-essential ubiquitin receptor for the 26S proteasome. Cells under significant stress or require significant ubiquitin-dependent degradation of proteins for survival, incorporate Rpn-13 in the 26S to increase protein degradation rates. The targeted protein degraders reported here are bifunctional molecules that include a ligand to Rpn-13 and BRD4, the protein of interest we wish to degrade. We synthesized a suite of degraders with varying PEG chain lengths and showed that bifunctional molecules that incorporate a Rpn-13 binder (TCL1) and a BRD4 binder (JQ1) with a PEG linker of 3 or 4 units are the most effective to induce BRD4 degradation. We also demonstrate that our new targeted protein degraders are dependent upon proteasome activity and Rpn-13 expression levels. This establishes a new mechanism of action for our ByeTACs that can be employed for the targeted degradation of a wide variety of protein substrates.

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“…This is because many PROTACs recruit E3 ligases that are expressed ubiquitously in both normal and tumor tissues, which can lead to on-target toxicities. However, researchers are exploring various strategies to enhance the selectivity of PROTACs for tumor-specific proteins of interest (POIs) to improve their therapeutic potential [ 83 ].…”

Section: Protacs: Targeted Management Strategy For Several Diseased C...mentioning

confidence: 99%

PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

Sincere,

Anand,

Ashique

et al. 2023

Molecules

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A potential therapeutic strategy to treat conditions brought on by the aberrant production of a disease-causing protein is emerging for targeted protein breakdown using the PROTACs technology. Few medications now in use are tiny, component-based and utilize occupancy-driven pharmacology (MOA), which inhibits protein function for a short period of time to temporarily alter it. By utilizing an event-driven MOA, the proteolysis-targeting chimeras (PROTACs) technology introduces a revolutionary tactic. Small-molecule-based heterobifunctional PROTACs hijack the ubiquitin–proteasome system to trigger the degradation of the target protein. The main challenge PROTAC’s development facing now is to find potent, tissue- and cell-specific PROTAC compounds with favorable drug-likeness and standard safety measures. The ways to increase the efficacy and selectivity of PROTACs are the main focus of this review. In this review, we have highlighted the most important discoveries related to the degradation of proteins by PROTACs, new targeted approaches to boost proteolysis’ effectiveness and development, and promising future directions in medicine.

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Proteolysis-Targeting Chimera (PROTAC): Is the Technology Looking at the Treatment of Brain Tumors?

Cited by 11 publications

References 123 publications

Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders

Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders

ByeTAC: Bypassing an E3 Ligase for Targeted Protein Degradation

PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

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