Опубликована: Окт. 28, 2024
is the most commonly mutated gene in cancer, but it remains recalcitrant to clinically meaningful therapeutic reactivation. We present here discovery and characterization of a small molecule chemical inducer proximity that activates mutant p53. named this compound TR anscriptional A ctivator p 53 (
Язык: Английский
Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(6), С. 2402 - 2427
Опубликована: Янв. 21, 2024
Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired PROTAC have not only revolutionized the landscape TPD but potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role this field. wide variety agents spanning broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which prove instrumental overcoming constraints conventional small molecule entities also provided rapidly renewing paradigms. Herein we summarize burgeoning non-small technological platforms PROTACs, three major trajectories, provide insights for design strategies based on novel
Язык: Английский
Процитировано
19
Chemical Society Reviews, Год журнала: 2024, Номер 53(10), С. 4838 - 4861
Опубликована: Янв. 1, 2024
In this review we highlight how the synthesis of degraders has evolved in recent years, particular application high-throughput chemistry and screening approaches such as D2B DEL technologies to expedite discovery timelines.
Язык: Английский
Процитировано
10
iScience, Год журнала: 2024, Номер 27(9), С. 110712 - 110712
Опубликована: Авг. 23, 2024
Small-molecule drugs are effective and thus most widely used. However, their applications limited by reliance on active high-affinity binding sites, restricting target options. A breakthrough approach involves molecular glues, a novel class of small-molecule compounds capable inducing protein-protein interactions (PPIs). This opens avenues to conventionally undruggable proteins, overcoming limitations seen in conventional drugs. Molecular glues play key role targeted protein degradation (TPD) techniques, including ubiquitin-proteasome system-based approaches such as proteolysis targeting chimeras (PROTACs) glue degraders recently emergent lysosome techniques like extracellular proteins through the asialoglycoprotein receptors (MoDE-As) macroautophagy (MADTACs). These enable an innovative strategy for prolonged inhibition pathology-associated proteins. review provides overview them, emphasizing clinical potential guiding development molecular-glue-mediated TPD techniques.
Язык: Английский
Процитировано
8
ACS Chemical Biology, Год журнала: 2023, Номер 18(12), С. 2464 - 2473
Опубликована: Ноя. 21, 2023
Molecular glue degraders (MGDs) are small molecules that degrade proteins of interest via the ubiquitin–proteasome system. While MGDs were historically discovered serendipitously, approaches for MGD discovery now include cell-viability-based drug screens or data mining public transcriptomics and response datasets. These approaches, however, have target spaces restricted to essential proteins. Here we develop a high-throughput workflow also reaches nonessential proteome. This begins with rapid synthesis compound library by sulfur(VI) fluoride exchange chemistry coupled morphological profiling assay in isogenic cell lines vary levels E3 ligase CRBN. By comparing changes induced treatment across lines, able identify FL2-14 as CRBN-dependent targeting protein GSPT2. We envision this would contribute characterization wider range
Язык: Английский
Процитировано
14
Journal of Chemical Information and Modeling, Год журнала: 2024, Номер 64(19), С. 7666 - 7678
Опубликована: Окт. 3, 2024
Proteolytic targeting chimeras (PROTACs), as an emerging type of drug, function by proximity-based modalities that narrow the distance between a target protein and E3 ubiquitin ligase to facilitate ubiquitination labeling for degradation. Although it is evidenced cooperativity PROTAC ternary interaction one key factors affecting degradation rate protein, design utilizing this indicator still challenging because complicated/flexible interactions in target-PROTAC-E3 system. Therefore, developing reliable practicable computational methods great interest design. Hence, study, we investigate feasibility using end-point binding free energy calculation method, represented molecular mechanics/Poisson-Boltzmann (generalized-Born) surface area (MM/PB(GB)SA), characterizing (including stabilization hook effects) systems. The result shows MM/GBSA good predictor these effects under relatively long dynamics adjustment (50-100 ns) low dielectric constant (ε
Язык: Английский
Процитировано
4
Опубликована: Фев. 12, 2024
We report a selection method of DNA-encoded libraries (DELs) that can identify the compounds able to induce ubiquitination protein intertest (POI). Since readout is based on POI ubiquitination, rather than binding or ternary complex formation, identified are more functionally relevant and predicative active degraders. In this study, by selecting DEL 950 different combinations ligands, linkers, E3 ligase ligands against BD1 domain bromodomain-containing 4 (BRD4-BD1) in presence absence ATP, we have potent BRD4-BD1 degrader (DC50: ~9.7 nM) also short-isoform-selective BRD4 0.26 μM). Furthermore, show formation may induced stable complexes but inactive This approach be an efficient broadly applicable for discovering functional degraders, as well harnessing vast chemical diversity DELs.
Язык: Английский
Процитировано
3
ACS Chemical Biology, Год журнала: 2024, Номер unknown
Опубликована: Сен. 12, 2024
Targeted protein degradation (TPD) is an emerging pharmacologic strategy. It relies on small-molecule "degraders" that induce proximity of a component E3 ubiquitin ligase complex and target to ubiquitination subsequent proteasomal degradation. Essentially, degraders thus expand the function ligases, allowing them degrade proteins they would not recognize in absence small molecule. Over past decade, insights gained from identifying, designing, characterizing various have significantly enhanced our understanding TPD mechanisms, precipitating rational degrader discovery strategies. In this Account, I aim explore how these can be extrapolated anticipate both opportunities challenges utilizing overarching concept proximity-inducing pharmacology manipulate other cellular circuits for dissection biological mechanisms therapeutic purposes.
Язык: Английский
Процитировано
3
Chemical Reviews, Год журнала: 2024, Номер 124(22), С. 12918 - 13019
Опубликована: Ноя. 7, 2024
O-Linked β-N-acetylglucosamine (O-GlcNAc) is an essential, dynamic monosaccharide post-translational modification (PTM) found on serine and threonine residues of thousands nucleocytoplasmic proteins. The installation removal O-GlcNAc controlled by a single pair enzymes, transferase (OGT) O-GlcNAcase (OGA), respectively. Since its discovery four decades ago, has been diverse classes proteins, playing important functional roles in many cellular processes. Dysregulation homeostasis implicated the pathogenesis disease, including neurodegeneration, X-linked intellectual disability (XLID), cancer, diabetes, immunological disorders. These foundational studies disease biology have motivated efforts to target therapeutically, with multiple clinical candidates under evaluation. In this review, we describe characterization biochemistry OGT OGA, regulation, development OGA inhibitors, pathophysiology, progress modulators, emerging opportunities for targeting O-GlcNAc. This comprehensive resource should motivate further study into function inspire strategies therapeutic modulation
Язык: Английский
Процитировано
3
Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown
Опубликована: Дек. 9, 2024
Abnormal phosphorylation of proteins can lead to various diseases, particularly cancer. Therefore, the development small molecules for precise regulation protein holds great potential drug design. While traditional kinase/phosphatase small-molecule modulators have shown some success, achieving has proven be challenging. The emergence heterobifunctional molecules, such as phosphorylation-inducing chimeric (PHICSs) and phosphatase recruiting chimeras (PHORCs), with proximity-inducing modalities is expected a breakthrough by specifically kinase or interest. Herein, we summarize targets aberrant in cancer underscore correcting therapy. Through reported cases targeting regulation, highlight current design strategies features these molecules. We also provide systematic elaboration link between aberrantly phosphorylated well existing challenges future research directions developing molecular drugs regulation.
Язык: Английский
Процитировано
3
Royal Society of Chemistry eBooks, Год журнала: 2025, Номер unknown, С. 134 - 156
Опубликована: Фев. 21, 2025
Targeted protein degradation (TPD) provides new therapeutic opportunities beyond traditional inhibitors. TPD relies on the ability to induce proximity between an E3 ligase and target of interest, harnessing ubiquitin proteasome system ubiquitylate degrade target. This can be induced by either monofunctional ligands (molecular glues) or bifunctional molecules that tether ligases together. DNA encoded libraries (DELs) provide rapid access diverse chemical space for ligand discovery and, their design, facilitate development both molecular glues degraders.
Язык: Английский
Процитировано
0