European Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 229, P. 114009 - 114009
Published: Nov. 22, 2021
Language: Английский
Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(7), P. 551 - 569
Published: May 17, 2021
Language: Английский
Citations
783
Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)
Published: April 4, 2022
Abstract Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application activity modulators, particularly inhibitors, has been the mainstream in development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology emerged as one most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. addition PROTAC, many different targeted degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), Antibody-based PROTAC (AbTAC), are emerging. These technologies have only greatly expanded scope TPD, also provided fresh insights into discovery. Here, we summarize advances major TPD technologies, discuss their potential applications, hope provide a prime for both biologists chemists who interested this vibrant field.
Language: Английский
Citations
420
Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)
Published: April 21, 2021
Abstract Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme enzyme that catalyzes the oxidation of L -tryptophan. Functionally, IDO1 has played pivotal role in cancer immune escape via catalyzing initial step kynurenine pathway, and overexpression also associated with poor prognosis various cancers. Currently, several small-molecule candidates peptide vaccines are currently being assessed clinical trials. Furthermore, “proteolysis targeting chimera” (PROTAC) technology been successfully used development degraders, providing novel therapeutics for Herein, we review biological functions IDO1, structural biology extensively summarize medicinal chemistry strategies inhibitors The emerging PROTAC-based degraders highlighted. This may provide comprehensive updated overview on their therapeutic potentials.
Language: Английский
Citations
257
ChemBioChem, Journal Year: 2021, Volume and Issue: 23(2)
Published: Sept. 8, 2021
Abstract Proteolysis‐targeting chimeras (PROTACs), an emerging paradigm‐shifting technology, hijacks the ubiquitin‐proteasome system for targeted protein degradation. PROTACs induce ternary complexes between E3 ligase and POI, this induced proximity leads to polyUb chain formation on substrates eventual proteasomal‐mediated POI have shown great therapeutic potential by degrading many disease‐causing proteins, such as androgen receptor BRD4. The PROTAC technology has advanced significantly in last two decades, with repertoire of targets increased tremendously. Herein, we describe recent developments focusing mechanistic kinetic studies, pharmacokinetic study, spatiotemporal control PROTACs, covalent resistance new ligands.
Language: Английский
Citations
159
Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(5), P. 350 - 367
Published: Jan. 25, 2022
Language: Английский
Citations
119
MedComm, Journal Year: 2023, Volume and Issue: 4(3)
Published: May 2, 2023
Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on backbones amino acid side chains proteins and expand diversity proteins, which provides basis for emergence organismal complexity. To date, more than 650 types protein modifications, such as most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain long-chain acylation redox irreversible have been described, inventory is still increasing. By changing conformation, localization, activity, stability, charges, interactions with other biomolecules, PTMs ultimately alter phenotypes biological processes cells. The homeostasis important human health. Abnormal may cause changes in properties loss functions, are closely related occurrence development various diseases. In this review, we systematically introduce characteristics, regulatory mechanisms, functions health addition, therapeutic prospects diseases by targeting associated enzymes also summarized. This work will deepen understanding promote discovery diagnostic prognostic markers drug targets
Language: Английский
Citations
119
Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)
Published: May 27, 2023
The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. most common form NCD is metabolic diseases, which affect people all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding the will generate novel targets for improved therapies across spectrum. Protein posttranslational modification (PTM) an important term that refers to biochemical specific amino acid residues in target proteins, immensely increases functional diversity proteome. range PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, several PTMs. Here, we offer review roles pathological consequences, including diabetes, obesity, fatty liver hyperlipidemia, atherosclerosis. Building upon this framework, afford description proteins pathways involved by focusing on PTM-based protein modifications, showcase pharmaceutical intervention preclinical studies clinical trials, future perspectives. Fundamental research defining mechanisms whereby regulate open new avenues therapeutic intervention.
Language: Английский
Citations
99
European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 235, P. 114290 - 114290
Published: March 15, 2022
Language: Английский
Citations
85
Medicinal Research Reviews, Journal Year: 2022, Volume and Issue: 42(3), P. 1280 - 1342
Published: Jan. 10, 2022
Abstract Proteolysis targeting chimaeras (PROTACs) is a cutting edge and rapidly growing technique for new drug discovery development. Currently, the largest challenge in molecular design development of PROTACs efficient identification potent drug‐like degraders. This review aims to comprehensively summarize analyse state‐of‐the‐art methods strategies PROTACs. We provide detailed illustration general principles tactics designing PROTACs, highlight representative case studies, discuss advantages limitations these strategies. Particularly, structure‐based rational PROTAC emerging types (e.g., homo‐PROTACs, multitargeting photo‐control PROTAC‐based conjugates) will be focused on.
Language: Английский
Citations
74
Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(24), P. 16033 - 16061
Published: Dec. 12, 2022
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route a prospective biological for treating various human diseases, such as tumors, neurodegenerative pulmonary fibrosis, diabetes. An increasing number clinical studies emphasize necessity developing novel molecules targeting PI3K/AKT/mTOR pathway. This review focuses on recent advances ATP-competitive inhibitors, allosteric covalent proteolysis-targeting chimeras against pathway, highlights possible solutions overcoming toxicities acquired drug resistance currently available drugs. We also provide recommendations future design development promising drugs
Language: Английский
Citations
74