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Drug Discovery Today Jan 2023Proteolysis targeting chimeras (PROTACs) have been extensively explored for targeted proteasomal degradation of disease-related proteins with enormous potential in the... (Review)
Review
Proteolysis targeting chimeras (PROTACs) have been extensively explored for targeted proteasomal degradation of disease-related proteins with enormous potential in the treatment of intractable diseases. However, PROTACs are poorly soluble and permeable bulky molecules facing several bioavailability challenges irrespective of the route of administration. Our review lays out crucial challenges in the delivery of target protein degraders and nanoformulation approaches to overcome physicochemical and biological hurdles that can aid in transporting these target-protein degraders to the disease site. We have elaborated on the current formulation approaches and further highlighted the prospective delivery strategies that could be probed for disease-specific targeted delivery of PROTACs.
Topics: Proteolysis; Proteolysis Targeting Chimera; Prospective Studies; Proteins
PubMed: 36184017
DOI: 10.1016/j.drudis.2022.103387 -
European Journal of Medicinal Chemistry Dec 2022Proteolysis targeting chimera (PROTAC) technology, one of the targeted protein degradation technologies, has drawn marked attention from researchers of both academia and... (Review)
Review
Proteolysis targeting chimera (PROTAC) technology, one of the targeted protein degradation technologies, has drawn marked attention from researchers of both academia and industry in recent years. After over two decades of development, the literature on it has proliferated. In order to better grasp the frontiers and hot spots of PROTAC, this bibliometric analysis was carried out. The articles and reviews regarding PROTAC were culled from the Web of Science Core Collection. General information and the trend of publication outputs, countries/regions, authors, journals, influential papers, and keywords in this field were visually analyzed using CtieSpace, VOSviewer, or Excel software. As a result, a total of 808 publications were included. The number of papers regarding PROTAC significantly increased yearly. These papers mainly come from 45 countries/regions led by the USA and China. 3886 authors were identified participating in these studies, among which Craig M. Crews had the most significant number and influential articles. Journal of Medicinal Chemistry and European Journal of Medicinal Chemistry are the two journals with the most papers. After analysis, the most influential papers were identified in the area, including highly cited papers, references with citation burst, and high co-citated papers. The most common keywords including cancer, E3 ligase, drug discovery, epigenetic, resistance, and so on, represent the current and developing areas of study. BRDs, androgen receptor (AR), HDACs, estrogen receptor (ER), EGFR, CDKs, and KRAS are the most common targets. At last, frontiers and challenges of PROTAC were discussed through the bibliometric analysis. This paper will be helpful for better understanding the frontiers and hotspots of PROTAC.
Topics: Bibliometrics; Proteolysis
PubMed: 36274273
DOI: 10.1016/j.ejmech.2022.114838 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Sep 2023Small-molecule anticancer drugs inhibited tumor growth based on targeted inhibition of specific proteins, while most of oncogenic proteins are "undruggable". Proteolysis... (Review)
Review
Small-molecule anticancer drugs inhibited tumor growth based on targeted inhibition of specific proteins, while most of oncogenic proteins are "undruggable". Proteolysis targeting chimeras (PROTAC) is an attractive and general strategy for treating cancer based on targeted degradation of oncogenic proteins. This review briefly describes the peptide-based PTOTAC and small molecule-based PROTAC. Subsequently, we summarize the development of targeted delivery of PROTAC, such as targeting molecule-mediated targeted delivery of PROTAC, nanomaterial-mediated targeted delivery of PROTAC and controllable activation of small-molecular PROTAC prodrug. Such strategies show potential application in improving tumor selectivity, overcoming off-target effect and reducing biotoxicity. At the end, the druggability of PROTAC is prospected.
Topics: Humans; Proteolysis Targeting Chimera; Nanostructures; Neoplasms; Proteolysis
PubMed: 37805843
DOI: 10.13345/j.cjb.230006 -
Pharmacology & Therapeutics Jun 2017Targeted protein degradation using the PROTAC technology is emerging as a novel therapeutic method to address diseases driven by the aberrant expression of a... (Review)
Review
Targeted protein degradation using the PROTAC technology is emerging as a novel therapeutic method to address diseases driven by the aberrant expression of a disease-causing protein. PROTAC molecules are bifunctional small molecules that simultaneously bind a target protein and an E3-ubiquitin ligase, thus causing ubiquitination and degradation of the target protein by the proteasome. Like small molecules, PROTAC molecules possess good tissue distribution and the ability to target intracellular proteins. Herein, we highlight the advantages of protein degradation using PROTACs, and provide specific examples where degradation offers therapeutic benefit over classical enzyme inhibition. Foremost, PROTACs can degrade proteins regardless of their function. This includes the currently "undruggable" proteome, which comprises approximately 85% of all human proteins. Other beneficial aspects of protein degradation include the ability to target overexpressed and mutated proteins, as well as the potential to demonstrate prolonged pharmacodynamics effect beyond drug exposure. Lastly, due to their catalytic nature and the pre-requisite ubiquitination step, an exquisitely potent molecules with a high degree of degradation selectivity can be designed. Impressive preclinical in vitro and in vivo PROTAC data have been published, and these data have propelled the development of clinically viable PROTACs. With the molecular weight falling in the 700-1000Da range, the delivery and bioavailability of PROTACs remain the largest hurdles on the way to the clinic. Solving these issues and demonstrating proof of concept clinical data will be the focus of many labs over the next few years.
Topics: Drug Delivery Systems; Drug Design; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Molecular Weight; Proteasome Endopeptidase Complex; Proteins; Proteolysis; Ubiquitination
PubMed: 28223226
DOI: 10.1016/j.pharmthera.2017.02.027 -
Chemical Society Reviews Jul 2022Targeted protein degradation (TPD) strategies have revolutionized how scientists tackle challenging protein targets deemed undruggable with traditional small molecule... (Review)
Review
Targeted protein degradation (TPD) strategies have revolutionized how scientists tackle challenging protein targets deemed undruggable with traditional small molecule inhibitors. Many promising campaigns to inhibit proteins have failed due to factors surrounding inhibition selectivity and targeting of compounds to specific tissues and cell types. One of the major improvements that PROTAC (proteolysis targeting chimera) and molecular glue technology can exert is highly selective control of target inhibition. Multiple studies have shown that PROTACs can gain selectivity for their protein targets beyond that of their parent ligands optimization of linker length and stabilization of ternary complexes. Due to the bifunctional nature of PROTACs, the tissue selective nature of E3 ligases can be exploited to uncover novel targeting mechanisms. In this review, we provide critical analysis of the recent progress towards making selective PROTAC molecules and new PROTAC technologies that will continue to push the boundaries of achieving selectivity. These efforts have wide implications in the future of treating disease as they will broaden the possible targets that can be addressed by small molecules, like undruggable proteins or broadly active targets that would benefit from degradation in specific tissue types.
Topics: Ligands; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35587208
DOI: 10.1039/d2cs00200k -
Current Pharmaceutical Design 2013
Topics: Disease; Health Status; Humans; Proteolysis
PubMed: 23016692
DOI: 10.2174/1381612811319060001 -
European Journal of Medicinal Chemistry May 2022Protein degradation technology has progressed dramatically since 2001 when proteolysis targeting chimera (PROTAC) was first reported. Various of distinctive degradation... (Review)
Review
Protein degradation technology has progressed dramatically since 2001 when proteolysis targeting chimera (PROTAC) was first reported. Various of distinctive degradation technologies based on PROTAC have been developed for the degradation of kinases, nuclear receptors, epigenetic proteins, misfolded proteins, and also RNAs, etc. These technologies greatly broaden the spectrum of targets and the scope of clinical applications for the treatment of cancer, neurodegenerative diseases and virus diseases, etc. More than 15 targeted degraders have been in the clinic to date. Here in this review, we summarized the constituents and examples of different degradation strategies, as well as their advantages and limitations.
Topics: Drug Discovery; Proteolysis; Technology
PubMed: 35307618
DOI: 10.1016/j.ejmech.2022.114290 -
Nature Reviews. Drug Discovery Dec 2019Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic...
Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.
Topics: Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Neoplasms; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 31666732
DOI: 10.1038/s41573-019-0047-y -
Drug Discovery Today. Technologies Apr 2019Proteolysis Targeting Chimeras (PROTACs) are a rapidly expanding new therapeutic modality inducing selective protein degradation and offering the potential of a... (Review)
Review
Proteolysis Targeting Chimeras (PROTACs) are a rapidly expanding new therapeutic modality inducing selective protein degradation and offering the potential of a differentiated pharmacological profile across multiple therapeutic areas. As the repertoire of protein targets and E3 ligases available for incorporation into PROTACs continues to grow, understanding the drug- and system-dependent parameters for PROTACs will be critical for achieving tissue/cell specific pharmacology. The review discusses the current knowledge and future direction of in vivo PROTAC study evaluation. The importance of establishing the quantitative relationship between loss of protein target and biological function in vivo, coupled with building mechanistic PK/PD and ultimately PBPK/PD models, is emphasised with the aim to aid translation from preclinical to clinical space.
Topics: Animals; Drug Evaluation, Preclinical; Humans; Models, Biological; Proteolysis; Translational Research, Biomedical
PubMed: 31200862
DOI: 10.1016/j.ddtec.2019.02.005 -
Environmental Science & Technology Apr 2020Proteins are a substantial nitrogen source in soils provided that they can be hydrolyzed into bioavailable small peptides or amino acids. However, the strong...
Proteins are a substantial nitrogen source in soils provided that they can be hydrolyzed into bioavailable small peptides or amino acids. However, the strong associations between proteins and soil minerals restrict such proteolytic reactions. This study focused on how an extracellular fungal protease ( sp.) hydrolyzed iron oxide-associated bovine serum albumin (BSA) and the factors that affected the proteolysis. We combined batch experiments with size-exclusion and reversed phase liquid chromatography and infrared spectroscopic measurements to monitor the generation of proteolytic products in solution as well as the real-time changes of the adsorbed BSA during 24 h. Results showed that protease hydrolyzed the iron oxide-associated BSA directly at the surface without an initial desorption of BSA. Concurrently, the protease was adsorbed to vacant surface sites at the iron oxides, which significantly slowed down the rate of proteolysis. This inhibiting effect was counteracted by the presence of preadsorbed phosphate or by increasing the BSA coverage, which prevented protease adsorption. Fast initial rates of iron oxide-associated BSA proteolysis, comparable to proteolysis of BSA in solution, and very slow rates at prolonged proteolysis suggest a large variability in mineral-associated proteins as a nitrogen source in soils and that only a fraction of the protein is bioavailable.
Topics: Adsorption; Ferric Compounds; Proteolysis; Serum Albumin, Bovine; Surface Properties
PubMed: 32208652
DOI: 10.1021/acs.est.0c00860