Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation

Chen, Yu; Tandon, Ira; Heelan, William John; Wang, Yixin; Tang, Weiping; Hu, Quanyin

doi:10.1039/d1cs00762a

Cited by 107 publications

(74 citation statements)

References 61 publications

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“…Since tumor immunotherapy is a multifactorial event, proteins in tumor cells, immune cells and tumor milieu can all be degraded by this novel technology. Future studies should develop more PROTAC molecules with preferable drug-like properties and expand their potency in immune modulation, while the following issues should be carefully taken into account: (i) More than “degrader”, PROTAC molecule can serve as an “intelligent switch” to program immune cells, which is exemplified by Park and co-workers [ 180 , 181 ]; (ii) certain targets had synchronous functions; therefore PROTAC molecules that simultaneously degraded two or more proteins are very promising [ 182 , 183 ]; (iii) E3 ligases CRBN and VHL are immuno-oncologic targets which can be degraded by homo-PROTAC strategies [ 184 , 185 , 186 ]; (iv) novel TPD strategies such as AUTAC, AbTAC, LYTAC and molecule glues have been developed to target extracellular and membrane proteins [ 187 , 188 ]; (v) advanced drug delivery systems (DDSs) including nanoparticles, polymetric micelles and liposomes can be leveraged to improve drug efficiency [ 189 , 190 ].…”

Section: Discussionmentioning

confidence: 99%

Small-Molecule PROTACs for Cancer Immunotherapy

Liu¹,

Zhang²,

Xiang³

et al. 2022

Molecules

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Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a Cancer Patients. Bosn. J. Basic novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

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Section: Discussionmentioning

confidence: 99%

Small-Molecule PROTACs for Cancer Immunotherapy

Liu¹,

Zhang²,

Xiang³

et al. 2022

Molecules

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“…Although numerous PROTACs reviews have been published, most of them are either general introductions to PROTACs or applications in specific areas of therapy. 12,18,29–35 However, how to rationally design PROTACs and optimize the structure-activity relationship is a major problem and challenge in this field. Some excellent reviews have presented brief rules and lessons for PROTACs design and optimization.…”

Section: Introductionmentioning

confidence: 99%

Chemistries of bifunctional PROTAC degraders

et al. 2022

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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%

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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Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation

Abstract: This tutorial review discusses the convergence of drug delivery systems and PROTACs, surveys the burgeoning PROTAC delivery strategies, summarizes their design principles, clarifies their challenges, and outlooks future translational opportunities.

Cited by 107 publications

References 61 publications

Small-Molecule PROTACs for Cancer Immunotherapy

Small-Molecule PROTACs for Cancer Immunotherapy

Chemistries of bifunctional PROTAC degraders

Solubility Enhanced Formulation Approaches to Overcome Oral Delivery Obstacles of PROTACs

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