Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3)....

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Vydané v:	Journal of hematology and oncology Ročník 13; číslo 1; s. 50 - 14
Hlavní autori:	Li, Xin, Song, Yongcheng
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London BioMed Central 13.05.2020 BioMed Central Ltd Springer Nature B.V BMC
Predmet:	Animals Antineoplastic agents Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Breast cancer Cancer Cancer Research Cancer therapies Cancer therapy Cancer treatment Cell growth Clinical trials Degradation Drug Discovery Drug dosages Gene expression Health aspects Hematological malignancies Hematology Humans Leukemia Ligands Ligases Lymphoma Medicine Medicine & Public Health Molecular Targeted Therapy Neoplasms - drug therapy Neoplasms - metabolism Nucleic acids Oncology Pharmacodynamics Pharmacokinetics PROTAC Proteasomes Proteins Proteolysis Proteolysis - drug effects Review RNA polymerase Targeted protein degradation Technology application Therapeutic targets Ubiquitin Ubiquitin-protein ligase Ubiquitination Ubiquitination - drug effects PROTAC Targeted protein degradation Cancer therapy Hematological malignancies
ISSN:	1756-8722, 1756-8722
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Popis
Shrnutí:	Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting ~ 50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. This article reviews PROTAC-mediated degradation of critical oncoproteins in cancer, particularly those in hematological malignancies. Chemical structures, cellular and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs are summarized. In addition, potential advantages, challenges, and perspectives of PROTAC technology in cancer therapy are discussed.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23
ISSN:	1756-8722 1756-8722
DOI:	10.1186/s13045-020-00885-3