2010159-56-3Relevant academic research and scientific papers
MICROMOLECULAR COMPOUND SPECIFICALLYDEGRADING TAU PROTEIN, AND APPLICATION THEREOF
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, (2022/01/12)
The present disclosure discloses a micromolecular compound specifically degrading tau protein, and an application thereof. The chemical structure of the micromolecular compound specifically degrading tau protein is TBM-L-ULM or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, TBM being a tau protein-binding moiety, L being a linking group, and ULM being a ubiquitin ligase-binding moiety, the tau protein-binding moiety and the ubiquitin ligase-binding moiety being connected by means of the linking group. The micromolecular compound specifically degrading tau protein may increase tau protein degradation in a cell, thereby decreasing tau protein content.
Development of BromoTag: A "bump-and-Hole"-PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins
Alessi, Dario R.,Blow, J. Julian,Bond, Adam G.,Chan, Kwok-Ho,Ciulli, Alessio,Craigon, Conner,Fasimoye, Rotimi,Karapetsas, Athanasios,MacArtney, Thomas,Testa, Andrea
, (2021/11/01)
Small-molecule-induced protein depletion technologies, also called inducible degrons, allow degradation of genetically engineered target proteins within cells and animals. Here, we design and develop the BromoTag, a new inducible degron system comprising a Brd4 bromodomain L387A variant as a degron tag that allows direct recruitment by heterobifunctional bumped proteolysis targeting chimeras (PROTACs) to hijack the VHL E3 ligase. We describe extensive optimization and structure-activity relationships of our bump-and-hole-PROTACs using a CRISPR knock-in cell line expressing model target BromoTag-Brd2 at endogenous levels. Collectively, our cellular and mechanistic data qualifies bumped PROTAC AGB1 as a potent, fast, and selective degrader of BromoTagged proteins, with a favorable pharmacokinetic profile in mice. The BromoTag adds to the arsenal of chemical genetic degradation tools allowing us to manipulate protein levels to interrogate the biological function and therapeutic potential in cells and in vivo.
Design, Synthesis, and Evaluation of Potent, Selective, and Bioavailable AKT Kinase Degraders
Cahuzac, Kaitlyn M.,Chen, Xian,Jin, Jian,Liu, Jing,Parsons, Ramon E.,Shen, Yudao,Wang, Li,Xie, Ling,Xu, Jia,Yu, Xufen
, p. 18054 - 18081 (2021/12/13)
The serine/threonine kinase AKT functions as a critical node of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (m-TOR) signaling pathway. Aberrant activation and overexpression of AKT are strongly correlated with numerous human cancers. To date, only two AKT degraders with no structure–activity relationship (SAR) results have been reported. Through extensive SAR studies on various linkers, E3 ligase ligands, and AKT binding moieties, we identified two novel and potent AKT proteolysis targeting chimera (PROTAC) degraders: von Hippel–Lindau (VHL)-recruiting degrader 13 (MS98) and cereblon (CRBN)-recruiting degrader 25 (MS170). These two compounds selectively induced robust AKT protein degradation, inhibited downstream signaling, and suppressed cancer cell proliferation. Moreover, these two degraders exhibited good plasma exposure levels in mice through intraperitoneal injection. Overall, our comprehensive SAR studies led to the discovery of degraders 13 and 25, which are potentially useful chemical tools to investigate biological and pathogenic functions of AKT in vitro and in vivo.
COMPOUNDS AND USES THEREOF
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, (2021/08/06)
The present disclosure features compounds and methods useful for the treatment of BAF complex-related disorders.
TROPOMYOSIN RECEPTOR KINASE (TRK) DEGRADATION COMPOUNDS AND METHODS OF USE
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Page/Page column 190; 196-197, (2021/09/04)
This disclosure relates to bivalent compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the bivalent compounds, and to methods of use the bivalent compounds for the treatment of certain disease in a subject in need thereof. The disclosure also relates to methods for identifying such bivalent compounds.
COMPOUNDS AND USES THEREOF
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Page/Page column 137-139, (2021/10/15)
The present disclosure features compounds useful for the treatment of BAF complex-related disorders.
CYCLIC-AMP RESPONSE ELEMENT BINDING PROTEIN (CBP) AND/OR ADENOVIRAL E1A BINDING PROTEIN OF 300 KDA (P300) DEGRADATION COMPOUNDS AND METHODS OF USE
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, (2020/09/12)
Bivalent compounds composition comprises one or more of the bivalent compounds. The bivalent compound comprises a cyclic-AMP response element binding protein (CBP) and/or adenoviral E1A binding protein of 300kDa (P300) ligand (CBP/P300 ligand) conjugated
TROPOMYOSIN RECEPTOR KINASE (TRK) DEGRADATION COMPOUNDS AND METHODS OF USE
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Page/Page column 100; 107, (2020/03/15)
Bivalent compounds, compositions comprising one or more of the bivalent compounds, and methods of use the bivalent compounds for the treatment of certain disease in a subject in need thereof are provided. Methods for identifying such bivalent compounds are provided, either.
COMPOUNDS AND METHODS OF TREATING CANCERS
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Page/Page column 95; 100, (2020/10/20)
This disclosure relates to heterobifunctional compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the heterobifunctional compounds, and to methods of use the heterobifunctional compounds for the treatment of ce
IRAK DEGRADERS AND USES THEREOF
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, (2019/07/10)
The present invention provides compounds, compositions thereof, and methods of using the same.
