Design, Synthesis, and Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair DOI
Man Zhao, Wenjing Ma,

Jimmy T. Liang

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 19428 - 19447

Published: Oct. 30, 2024

Proteolytic targeting chimera (PROTAC) represent an advanced strategy for undruggable proteins, and the molecular warheads E3 ligases play a crucial role. Recently, we explored alkenyl oxindole warhead ligase DCAF11 sought to validate its potential. In this study, synthesized range of BRD4 PROTACs (8a–8o, 14a–14f, 22a–22m) with modified developed high-throughput screening system based on high-content imaging. We identified L134 (22a) as potent degrader, achieving degradation (Dmax > 98%, DC50 = 7.36 nM) demonstrating antitumor activity. Mechanically, by was mediated through ubiquitin-proteasome in DCAF11-dependent manner. Therefore, study provides rapid method effective highlights PROTAC oxindole-DCAF11 pair promising candidate treating BRD4-driven cancers.

Language: Английский

R406 and its structural analogs reduce SNCA/α-synuclein levels via autophagic degradation DOI Creative Commons
Chao Zhong, Xiaoge Gao, Qi Chen

et al.

Autophagy, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

The presence of neuronal Lewy bodies mainly composed SNCA/α-synuclein aggregations is a pathological feature Parkinson disease (PD), whereas reducing SNCA protein levels may slow the progression this disease. We hypothesized that compounds enhancing SNCA's interaction with MAP1LC3/LC3 May increase its macroautophagic/autophagic degradation. Here, we conducted small molecule microarray (SMM)-based screening to identify such and revealed compound R406 could decrease in an autophagy-dependent manner. further validated proposed mechanism, which knockdown essential gene ATG5 for autophagy formation using inhibitor chloroquine (CQ) blocked effect R406. Additionally, also reduced phosphorylated serine 129 (p-S129-SNCA) preformed fibrils (PFFs)-induced cellular models rescued neuron degeneration.

Language: Английский

Citations

0
New therapies on the horizon: Targeted protein degradation in neuroscience DOI Creative Commons

James A Gregory,

Christopher M. Hickey, Juan D. Chavez

et al.

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(9), P. 1688 - 1698

Published: Sept. 1, 2024

Language: Английский

Citations

3
Design, Synthesis, and Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair DOI
Man Zhao, Wenjing Ma,

Jimmy T. Liang

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 19428 - 19447

Published: Oct. 30, 2024

Proteolytic targeting chimera (PROTAC) represent an advanced strategy for undruggable proteins, and the molecular warheads E3 ligases play a crucial role. Recently, we explored alkenyl oxindole warhead ligase DCAF11 sought to validate its potential. In this study, synthesized range of BRD4 PROTACs (8a–8o, 14a–14f, 22a–22m) with modified developed high-throughput screening system based on high-content imaging. We identified L134 (22a) as potent degrader, achieving degradation (Dmax > 98%, DC50 = 7.36 nM) demonstrating antitumor activity. Mechanically, by was mediated through ubiquitin-proteasome in DCAF11-dependent manner. Therefore, study provides rapid method effective highlights PROTAC oxindole-DCAF11 pair promising candidate treating BRD4-driven cancers.

Language: Английский

Citations

0