Drug delivery challenges and formulation aspects of proteolysis targeting chimera (PROTACs)

Saraswat, Aishwarya; Vartak, Richa; Hegazy, Rehab A.; Patel, Akanksha; Patel, Ketan

doi:10.1016/j.drudis.2022.103387

Cited by 26 publications

(17 citation statements)

References 62 publications

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“…PROTACs represent a new and very promising class of compounds to treat multiple chronic diseases and offer new pharmaceutical opportunities by targeting undruggable proteins. However, their physicochemical properties suspect minimal oral bioavailability, resulting in limited clinical effectiveness [ 3 , 8 , 38 ]. The investigated PROTAC ARCC-4 is a typical representative of this class.…”

Section: Discussionmentioning

confidence: 99%

“…As poor aqueous solubility is the main limiting factor contributing to the low bioavailability of lipophilic drugs in peroral formulations, developing strategies to overcome the low solubility is necessary [ 6 , 7 ]. In the case of solubility-enhancing peroral applications of PROTACs, recent studies focused on self-emulsifying drug delivery systems [ 8 ]. For instance, Rathod et al developed PROTAC-loaded self-nano emulsifying preconcentrate using ARV-825 as PROTAC molecule (ARV-SNEP) and significantly enhanced solubility in aqueous and biorelevant media [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Solubility Enhanced Formulation Approaches to Overcome Oral Delivery Obstacles of PROTACs

et al. 2023

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PROteolysis TArgeting Chimaeras (PROTACs) offer new opportunities in modern medicine by targeting proteins that are undruggable to classic inhibitors. However, due to their hydrophobic structure, PROTACs typically suffer from low solubility, and oral bioavailability remains challenging. At the same time, due to their investigative state, the drug supply is meager, leading to limited possibilities in terms of formulation development. Therefore, we investigated the solubility enhancement employing mini-scale formulations of amorphous solid dispersions (ASDs) and liquisolid formulations of the prototypic PROTAC ARCC-4. Based on preliminary supersaturation testing, HPMCAS (L Grade) and Eudragit® L 100-55 (EL 100-55) were demonstrated to be suitable polymers for supersaturation stabilization of ARCC-4. These two polymers were selected for preparing ASDs via vacuum compression molding (VCM), using drug loads of 10 and 20%, respectively. The ASDs were subsequently characterized with respect to their solid state via differential scanning calorimetry (DSC). Non-sink dissolution testing revealed that the physical mixtures (PMs) did not improve dissolution. At the same time, all ASDs enabled pronounced supersaturation of ARCC-4 without precipitation for the entire dissolution period. In contrast, liquisolid formulations failed in increasing ARCC-4 solubility. Hence, we demonstrated that ASD formation is a promising principle to overcome the low solubility of PROTACs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Solubility Enhanced Formulation Approaches to Overcome Oral Delivery Obstacles of PROTACs

et al. 2023

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“…Nanomedicine has raised many expectations to improve the bioavailability of PROTACs. Encapsulating PROTACs for the generation of "nanoPROTACs" would increase the cellular uptake and solubility of PROTACs [161]. Recently, researchers have constructed various nanocarriers incorporating ARV-825 for treatment of melanoma, pancreatic cancer and non-small-cell lung cancer [162][163][164].…”

Section: Therapeutic Potential For the Pcd-associated Diseases By Tar...mentioning

confidence: 99%

“…Furthermore, since PROTACs can be recycled and used for multiple rounds of target protein degradation, compared to their parent BETi, much lower concentrations of PROTACs can achieve profound therapeutic effects [ 153 , 160 ]. However, PROTACs are large molecules with poor solubility and cell permeability, limiting their bioavailability [ 161 ]. Nanomedicine has raised many expectations to improve the bioavailability of PROTACs.…”

Section: Introductionmentioning

confidence: 99%

Regulation of programmed cell death by Brd4

Pan

et al. 2022

Cell Death Dis

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Epigenetic factor Brd4 has emerged as a key regulator of cancer cell proliferation. Targeted inhibition of Brd4 suppresses growth and induces apoptosis of various cancer cells. In addition to apoptosis, Brd4 has also been shown to regulate several other forms of programmed cell death (PCD), including autophagy, necroptosis, pyroptosis, and ferroptosis, with different biological outcomes. PCD plays key roles in development and tissue homeostasis by eliminating unnecessary or detrimental cells. Dysregulation of PCD is associated with various human diseases, including cancer, neurodegenerative and infectious diseases. In this review, we discussed some recent findings on how Brd4 actively regulates different forms of PCD and the therapeutic potentials of targeting Brd4 in PCD-related human diseases. A better understanding of PCD regulation would provide not only new insights into pathophysiological functions of PCD but also provide new avenues for therapy by targeting Brd4-regulated PCD.

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“…A key consideration in the development of PROTAC drugs is selecting an appropriate combination of ligands for the E3 ligase and the target protein [12,13]. In this context, the use of computational strategies to understand the interaction between PROTACs and the E3 ligase and/or target protein can aid in the rational design, screening, and optimization of drugs [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Computational strategies for PROTAC drug discovery

Wang

Leung

2023

Acta Materia Medica

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Proteolysis-targeting chimeras (PROTACs), a novel targeted protein degradation technology for potential clinical drug discovery, is composed of a protein-targeting ligand covalently linked to an E3 ligase ligand. Through recruiting E3 ligase to target proteins, PROTACs elicit ubiquitination and subsequent degradation of targets via the ubiquitin-proteasome system. In the past few decades, molecular docking and virtual screening have emerged as an efficient strategy in drug discovery for identifying compounds from a large database of chemical structures. For PROTACs, molecular docking accurately simulates the protein-PROTAC-E3 ternary complex, thus greatly accelerating structure-activity-relationship analysis, and improving ligand affinity and selectivity. In this review, we summarize recent efforts in the application of molecular docking and virtual screening for PROTAC drug discovery. To date, approximately nine target proteins and twelve PROTACs have been successfully developed through molecular docking and virtual screening. Finally, the potential challenges of molecular docking and virtual screening-based PROTACs are discussed.

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Drug delivery challenges and formulation aspects of proteolysis targeting chimera (PROTACs)

Cited by 26 publications

References 62 publications

Solubility Enhanced Formulation Approaches to Overcome Oral Delivery Obstacles of PROTACs

Solubility Enhanced Formulation Approaches to Overcome Oral Delivery Obstacles of PROTACs

Regulation of programmed cell death by Brd4

Computational strategies for PROTAC drug discovery

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