PROTAC targeted protein degraders: the past is prologue

Nature Reviews Drug Discovery, Год журнала: 2022, Номер 21(3), С. 181 - 200

Опубликована: Янв. 18, 2022

Язык: Английский

---

Targeting transcription factors in cancer — from undruggable to reality

Nature reviews. Cancer, Год журнала: 2019, Номер 19(11), С. 611 - 624

Опубликована: Сен. 11, 2019

Язык: Английский

---

The role of ubiquitination in tumorigenesis and targeted drug discovery

Signal Transduction and Targeted Therapy, Год журнала: 2020, Номер 5(1)

Опубликована: Фев. 29, 2020

Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" "quality" various proteins, serving to ensure cell homeostasis guarantee life activities. The regulation ubiquitination is multifaceted works not only at transcriptional levels (phosphorylation, acetylation, methylation, etc.) but also level (activators or repressors). When regulatory mechanisms are aberrant, altered biological processes may induce serious human diseases, especially types cancer. In tumorigenesis, involve tumor metabolism, immunological microenvironment (TME), cancer stem (CSC) stemness so on. With regard some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc P53 significantly regulates activity mTORC1, AMPK PTEN-AKT signaling pathways. addition, TLR, RLR STING-dependent pathways modulates TME. Moreover, core regulator triplets (Nanog, Oct4 Sox2) members Wnt Hippo-YAP participates maintenance CSC stemness. Based on components, including proteasome, E3 ligases, E1, E2 deubiquitinases (DUBs), many molecular targeted drugs have been developed combat Among them, small molecule inhibitors targeting bortezomib, carfilzomib, oprozomib ixazomib, achieved tangible success. MLN7243 MLN4924 (targeting E1 enzyme), Leucettamol A CC0651 nutlin MI-219 compounds G5 F6 DUB activity) shown potential preclinical treatment. this review, we summarize latest progress understanding substrates for their special functions metabolism regulation, TME modulation maintenance. therapeutic targets reviewed, effects drugs.

Язык: Английский

---

N-degron and C-degron pathways of protein degradation

Proceedings of the National Academy of Sciences, Год журнала: 2019, Номер 116(2), С. 358 - 366

Опубликована: Янв. 7, 2019

This perspective is partly review and proposal. N-degrons C-degrons are degradation signals whose main determinants are, respectively, the N-terminal C-terminal residues of cellular proteins. include, to varying extents, adjoining sequence motifs, also internal lysine that function as polyubiquitylation sites. Discovered in 1986, were first short-lived A particularly large set was discovered 2018. We describe multifunctional proteolytic systems target C-degrons. propose denote these “N-degron pathways” “C-degron pathways.” The former notation replaces earlier name “N-end rule term rule” introduced 33 years ago, when only some thought be destabilizing. However, studies over last three decades have shown all 20 amino acids genetic code can act, cognate contexts, destabilizing residues. Advantages proposed terms include their brevity semantic uniformity for In addition being topologically analogous, related functionally. cleavage a subunit multisubunit complex create, at same time, an N-degron (in fragment) spatially adjacent C-degron fragment). Consequently, both fragments selectively destroyed through attacks by pathways.

Язык: Английский

---

Targeted protein degradation: elements of PROTAC design

Current Opinion in Chemical Biology, Год журнала: 2019, Номер 50, С. 111 - 119

Опубликована: Апрель 17, 2019

Язык: Английский

---

Deciphering molecular interactions by proximity labeling

Nature Methods, Год журнала: 2021, Номер 18(2), С. 133 - 143

Опубликована: Янв. 11, 2021

Язык: Английский

---

Development of targeted protein degradation therapeutics

Nature Chemical Biology, Год журнала: 2019, Номер 15(10), С. 937 - 944

Опубликована: Сен. 16, 2019

Язык: Английский

---

The Ubiquitin System, Autophagy, and Regulated Protein Degradation

Annual Review of Biochemistry, Год журнала: 2017, Номер 86(1), С. 123 - 128

Опубликована: Июнь 20, 2017

This brief disquisition about the early history of studies on regulated protein degradation introduces several detailed reviews ubiquitin system and autophagy.

Язык: Английский

---

Regulating IRFs in IFN Driven Disease

Frontiers in Immunology, Год журнала: 2019, Номер 10

Опубликована: Март 29, 2019

The Interferon regulatory factors (IRFs) are a family of transcription that play pivotal roles in many aspects the immune response, including cell development and differentiation regulating responses to pathogens. Three members, IRF3, IRF5 IRF7, critical production type I interferons downstream pathogen recognition receptors detect viral RNA DNA. A fourth member, IRF9, regulates interferon-driven gene expression. In addition, IRF4, IRF8 regulate myeloid phenotype, thus playing important inflammatory responses. Thus understanding how their levels activity is regulated importance given perturbations either can result dysregulated potential autoimmune disease. This review will focus role IRF members IFN or differentiation, with particular emphasis on regulation by ubiquitination microRNAs may impact

Язык: Английский

---

RCSB Protein Data Bank: Enabling biomedical research and drug discovery

Protein Science, Год журнала: 2019, Номер 29(1), С. 52 - 65

Опубликована: Сен. 18, 2019

Abstract Analyses of publicly available structural data reveal interesting insights into the impact three‐dimensional (3D) structures protein targets important for discovery new drugs (e.g., G‐protein‐coupled receptors, voltage‐gated ion channels, ligand‐gated transporters, and E3 ubiquitin ligases). The Protein Data Bank (PDB) archive currently holds > 155,000 atomic‐level 3D biomolecules experimentally determined using crystallography, nuclear magnetic resonance spectroscopy, electron microscopy. PDB was established in 1971 as first open‐access, digital‐data resource biology, is now managed by Worldwide partnership (wwPDB; wwPDB.org ). US operations are responsibility Research Collaboratory Structural Bioinformatics (RCSB PDB). RCSB serves millions RCSB.org users worldwide delivering integrated with ∼40 external biodata resources, providing rich views fundamental biomedicine, energy sciences. Recently published work showed that archival holdings facilitated ∼90% 210 approved Food Drug Administration 2010–2016. We review user‐driven development services, examine growth terms size complexity, present examples opportunities structure‐guided drug challenging integral membrane proteins).

Язык: Английский

---