Cited by The ubiquitin-proteasome system in the regulation of tumor dormancy and recurrence

Rapid PROTAC Discovery Platform: Nanomole-Scale Array Synthesis and Direct Screening of Reaction Mixtures DOI

Mateusz P. Plesniak,

Emilia K. Taylor,

Frederik Eisele

и другие.

ACS Medicinal Chemistry Letters, Год журнала: 2023, Номер 14(12), С. 1882 - 1890

Опубликована: Ноя. 11, 2023

Precise length, shape, and linker attachment points are all integral components to designing efficacious proteolysis targeting chimeras (PROTACs). Due the synthetic complexity of these heterobifunctional degraders difficulty computational modeling aid PROTAC design, exploration structure–activity relationships remains mostly empirical, which requires a significant investment time resources. To facilitate rapid hit finding, we developed capabilities for parallel synthesis purification by harnessing an array preformed E3-ligand-linker intermediates. In next iteration this approach, rapid, nanomole-scale methodology using amide coupling that enables direct screening nonpurified reaction mixtures in cell-based degradation assays, as well logD EPSA measurements. This approach greatly expands accelerates SAR (5 days instead several weeks) avoids laborious solvent-demanding mixtures, thus making it economical more sustainable finding.

Язык: Английский

Процитировано

Revolutionizing Drug Targeting Strategies: Integrating Artificial Intelligence and Structure-Based Methods in PROTAC Development DOI

Mohd Danishuddin,

Mohammad Sarwar Jamal, Kyoung Seob Song

и другие.

Pharmaceuticals, Год журнала: 2023, Номер 16(12), С. 1649 - 1649

Опубликована: Ноя. 24, 2023

PROteolysis TArgeting Chimera (PROTAC) is an emerging technology in chemical biology and drug discovery. This technique facilitates the complete removal of target proteins that are "undruggable" or challenging to through molecules via Ubiquitin-Proteasome System (UPS). PROTACs have been widely explored outperformed not only cancer but also other diseases. During past few decades, several academic institutes pharma companies poured more efforts into PROTAC-related technologies, setting stage for major degrader trial readouts clinical phases. Despite their promising results, formation robust ternary orientation, off-target activity, poor permeability, binding affinity some limitations hinder development. Recent advancements computational technologies facilitated progress development PROTACs. Researchers able utilize these explore a wider range E3 ligases optimize linkers, thereby gaining better understanding effectiveness safety settings. In this review, we briefly strategies reported date PROTAC components discuss key challenges opportunities further research area.

Язык: Английский

Процитировано

Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins DOI

Simonne Griffith-Jones, Lucı́a Álvarez, Urbi Mukhopadhyay

и другие.

The EMBO Journal, Год журнала: 2024, Номер 43(7), С. 1273 - 1300

Опубликована: Март 6, 2024

Abstract MAGEA4 is a cancer-testis antigen primarily expressed in the testes but aberrantly overexpressed several cancers. interacts with RING ubiquitin ligase RAD18 and activates trans-lesion DNA synthesis (TLS), potentially favouring tumour evolution. Here, we employed NMR AlphaFold2 (AF) to elucidate interaction mode between MAGEA4, reveal that RAD6-binding domain (R6BD) of occupies groove C-terminal winged-helix subdomain MAGEA4. We found partially displaces RAD6 from R6BD inhibits degradative autoubiquitination, which could be countered by competing peptide R6BD. cross-linking mass spectrometry (XL-MS) also revealed an evolutionary invariant intramolecular catalytic DNA-binding SAP domains RAD18, essential for PCNA mono-ubiquitination. Using proteomics, another Type-I MAGE, MAGE-C2, TRIM28 manner similar MAGEA4/RAD18 complex, suggesting peptide-binding serves as ligase-binding cleft other type-I MAGEs. Our data provide new insights into mechanism regulation RAD18-mediated

Язык: Английский

Процитировано

Ubiquitin E3 ligases assisted technologies in protein degradation: Sharing pathways in neurodegenerative disorders and cancer DOI

Aastha Kaushik,

Somya Parashar,

Rashmi K. Ambasta

и другие.

Ageing Research Reviews, Год журнала: 2024, Номер 96, С. 102279 - 102279

Опубликована: Март 22, 2024

Язык: Английский

Процитировано

The ubiquitin-proteasome system in the regulation of tumor dormancy and recurrence DOI

Bashar A. Alhasan, А. В. Морозов, Irina V. Guzhova

и другие.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2024, Номер 1879(4), С. 189119 - 189119

Опубликована: Май 16, 2024

Язык: Английский

Процитировано