Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 30, 2023

Targeted proteasomal and autophagic protein degradation, often employing bifunctional modalities, is a new paradigm for modulation of function. In an attempt to explore degradation by means autophagy we combine arylidene-indolinones reported bind the autophagy-related LC3B-protein ligands PDEδ lipoprotein chaperone, BRD2/3/4-bromodomain containing proteins BTK- BLK kinases. Unexpectedly, resulting degraders do not induce macroautophagy, but instead direct their targets ubiquitin-proteasome system. Target mechanism identification reveal that covalently DCAF11, substrate receptor in CUL4A/B-RBX1-DDB1-DCAF11 E3 ligase. The tempered α, β-unsaturated indolinone electrophiles define drug-like DCAF11-ligand class enables exploration this ligase chemical biology medicinal chemistry programs. arylidene-indolinone scaffold frequently occurs natural products which raises question whether ligand classes can be found more widely among related compounds.

Language: Английский

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Application of Novel Degraders Employing Autophagy for Expediting Medicinal Research

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(3), P. 1700 - 1711

Published: Jan. 30, 2023

Targeted protein degradation (TPD) technology is based on a unique pharmacological mechanism that has profoundly revolutionized medicinal research by overcoming limitations associated with traditional small-molecule drugs. Autophagy, for intracellular waste disposal and recovery, an important biological process in research. Recently, studies have demonstrated several emerging autophagic degraders can treat human diseases. Herein we summarize the progress degraders, including autophagosome-tethering compounds (ATTEC), autophagy-targeting chimeras (AUTAC), AUTOphagy-TArgeting (AUTOTAC), treating These exhibit excellent potential neurodegenerative Our provides new avenue TPD via autophagy.

Language: Английский

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Recent advances in targeted protein degraders as potential therapeutic agents

Molecular Diversity, Journal Year: 2023, Volume and Issue: 28(1), P. 309 - 333

Published: Feb. 15, 2023

Language: Английский

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Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(4), P. 2466 - 2486

Published: Feb. 5, 2024

Adenoviral E1A binding protein 300 kDa (p300) and its closely related paralog CREB (CBP) are promising therapeutic targets for human cancer. Here, we report the first discovery of novel potent small-molecule PROTAC degraders p300/CBP against hepatocellular carcinoma (HCC), one most common solid tumors. Based upon clinical bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize linker generate series PROTACs, culminating in identification QC-182. This compound effectively induces degradation SK-HEP-1 HCC cells dose-, time-, ubiquitin-proteasome system-dependent manner. QC-182 significantly downregulates p300/CBP-associated transcriptome cells, leading more cell growth inhibition compared parental inhibitors reported degrader dCBP-1. Notably, potently depletes proteins mouse xenograft tumor tissue. is lead toward development p300/CBP-targeted therapy.

Language: Английский

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Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: 45(8), P. 1740 - 1751

Published: April 12, 2024

Language: Английский

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