Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation

Cancer Cell, Год журнала: 2019, Номер 36(2), С. 194 - 209.e9

Опубликована: Авг. 1, 2019

Язык: Английский

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Antibody–PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4

ACS Chemical Biology, Год журнала: 2020, Номер 15(6), С. 1306 - 1312

Опубликована: Апрель 27, 2020

Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness PROTACs against a wide variety targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells different types. Here, we describe strategy for selective specific cell type. We report design synthesis trastuzumab-PROTAC conjugate (Ab-PROTAC 3) which E3 ligase-directed degrader activity caged antibody linker can be hydrolyzed following antibody–PROTAC internalization, releasing active PROTAC inducing catalytic degradation. show that 3 selectively bromodomain-containing 4 (BRD4) only HER2 positive breast cancer lines, while sparing negative cells. Using live confocal microscopy, internalization lysosomal trafficking specifically cells, leading release quantities sufficient induce potent BRD4 These studies demonstrate proof-of-concept tissue-specific degradation, overcoming limitations selectivity, significant potential application novel targets.

Язык: Английский

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Patch-Seq Links Single-Cell Transcriptomes to Human Islet Dysfunction in Diabetes

Cell Metabolism, Год журнала: 2020, Номер 31(5), С. 1017 - 1031.e4

Опубликована: Апрель 16, 2020

Язык: Английский

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Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery

Journal of Medicinal Chemistry, Год журнала: 2021, Номер 64(15), С. 10606 - 10620

Опубликована: Июль 28, 2021

Targeted protein degradation is a promising area in the discovery and development of innovative therapeutics. Molecular glues mediate proximity-induced have intrinsic advantages over heterobifunctional proteolysis-targeting chimeras, including unprecedented mechanisms, distinct biological activities, favorable physicochemical properties. Classical molecular glue degraders been identified serendipitously, but rational design strategies are emerging rapidly. In this review, we aim to highlight recent advances for targeted discuss challenges developing into therapeutic agents. particular, strategies, action representative case studies will be addressed.

Язык: Английский

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Multispecific drugs herald a new era of biopharmaceutical innovation

Nature, Год журнала: 2020, Номер 580(7803), С. 329 - 338

Опубликована: Апрель 15, 2020

Язык: Английский

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