Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel–Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7

Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 62(2), P. 699 - 726

Published: Dec. 12, 2018

Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be lengthy unpredictable process, it remains unclear whether any combination might productive for degradation. We describe probe-quality degrader ligase–target pair deemed unsuitable: von Hippel–Lindau (VHL) BRD9, bromodomain-containing subunit SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns linkers monitoring cellular degradation activities, kinetic profiles, ubiquitination, as well ternary formation thermodynamics. The emerged structure–activity relationships guided discovery VZ185, potent, fast, selective BRD9 its close homolog BRD7. Our findings qualify new chemical tool BRD7/9 knockdown provide roadmap PROTAC development against seemingly incompatible target–ligase combinations.

Language: Английский

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Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development

Cell, Journal Year: 2020, Volume and Issue: 183(6), P. 1714 - 1731.e10

Published: Dec. 1, 2020

Language: Английский

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MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53

Cancer Research, Journal Year: 2018, Volume and Issue: 79(1), P. 251 - 262

Published: Nov. 1, 2018

Abstract Although the number of proteins effectively targeted for posttranslational degradation by PROTAC has grown steadily, E3 ligases successfully exploited to accomplish this been limited few which small-molecule ligands have discovered. ligase MDM2 is bound nutlin class ligands, there are nutlin-based PROTAC. Because a should both knockdown its target protein and upregulate tumor suppressor p53, we examined ability such decrease cancer cell viability. A nutlin-based, BRD4-degrading PROTAC, A1874, was able degrade 98% with nanomolar potency. Given complementary A1874 stabilize discovered that more effective in inhibiting proliferation many lines wild-type p53 than corresponding VHL-utilizing similar potency efficacy BRD4. This first report ligand targeting warhead combine exert synergistic antiproliferative effect. Our study highlights untapped potential may be unlocked expanding repertoire can recruited Significance: These findings present BRD4-targeting MDM2-based possesses potent, distinct, biological activities associated ends heterobifunctional molecule.

Language: Английский

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Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action

ACS Chemical Biology, Journal Year: 2018, Volume and Issue: 13(9), P. 2758 - 2770

Published: Aug. 23, 2018

A new generation of heterobifunctional small molecules, termed proteolysis targeting chimeras (PROTACs), targets proteins for degradation through recruitment to E3 ligases and holds significant therapeutic potential. Despite numerous successful examples, PROTAC molecule development remains laborious unpredictable, involving testing compounds end-point activity at fixed times concentrations without resolving or optimizing the important biological steps required process. Given complexity ubiquitin proteasomal pathway, technologies that enable real-time characterization efficacy mechanism action are critical accelerating compound development, profiling, improving guidance chemical structure-activity relationship. Here, we present an innovative, modular live-cell platform utilizing endogenous tagging apply it monitoring PROTAC-mediated bromodomain extra-terminal family members. We show comprehensive recovery profiles each target, precisely quantifying rates, maximal levels ( Dmax), time frame Dmax. These metrics specific member-dependent responses closely associated with key cellular protein interactions Kinetic studies ternary complex stability influences potency efficacy. Meanwhile, level ubiquitination is highly correlated rate, indicating stemming from productive formation main driver rate. The approaches applied here highlight which choice ligase handle can elicit different outcomes discern individual parameters degradation, ultimately enabling design strategies rank ordering potential compounds.

Language: Английский

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Degradation of proteins by PROTACs and other strategies

Acta Pharmaceutica Sinica B, Journal Year: 2019, Volume and Issue: 10(2), P. 207 - 238

Published: Aug. 13, 2019

Blocking the biological functions of scaffold proteins and aggregated is a challenging goal. PROTAC proteolysis-targeting chimaera (PROTAC) technology may be solution, considering its ability to selectively degrade target proteins. Recent progress in strategy include identification structure first ternary eutectic complex, extra-terminal domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), ARV-110 has entered clinical trials for treatment prostate cancer 2019. These discoveries strongly proved value strategy. In this perspective, we summarized recent meaningful research PROTAC, including types degradation proteins, preliminary data vitro vivo, new E3 ubiquitin ligases. Importantly, molecular design, optimization application candidate molecules are highlighted detail. Future perspectives development advanced medical fields have also been discussed systematically.

Language: Английский

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Exploring Targeted Degradation Strategy for Oncogenic KRASG12C

Cell chemical biology, Journal Year: 2019, Volume and Issue: 27(1), P. 19 - 31.e6

Published: Dec. 26, 2019

Language: Английский

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Transcription-Associated Cyclin-Dependent Kinases as Targets and Biomarkers for Cancer Therapy

Cancer Discovery, Journal Year: 2020, Volume and Issue: 10(3), P. 351 - 370

Published: Feb. 18, 2020

Drugs targeting the cell cycle-regulatory cyclin-dependent kinase (CDK) 4 and 6 have been approved for treatment of hormone receptor-positive breast cancer, inhibitors other cell-cycle CDKs are currently in clinical trials. Another class CDKs, transcription-associated including CDK7, CDK8, CDK9, CDK12 CDK13, critical regulators gene expression. Recent evidence suggests several novel functions these regulation epigenetic modifications, intronic polyadenylation, DNA-damage responses, genomic stability. Here, we summarize our current understanding transcriptional their utility as biomarkers, potential therapeutic targets. SIGNIFICANCE: CDK CDK4 CDK6 Several studies now point to opportunities by inhibiting well vulnerabilities with PARP immunotherapy tumors deficient CDKs.

Language: Английский

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Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs

ACS Central Science, Journal Year: 2019, Volume and Issue: 5(10), P. 1682 - 1690

Published: Sept. 17, 2019

Off-tissue effects are persistent issues of modern inhibition-based therapies. By merging the strategies photopharmacology and small-molecule degraders, we introduce a novel concept for spatiotemporal control induced protein degradation that potentially prevents off-tissue toxicity. Building on successful principle bifunctional all-small-molecule Proteolysis Targeting Chimeras (PROTACs), designed photoswitchable PROTACs (

Language: Английский

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PHOTACs enable optical control of protein degradation

Science Advances, Journal Year: 2020, Volume and Issue: 6(8)

Published: Feb. 21, 2020

We present a modular approach to control the small molecule–mediated degradation of cellular proteins interest using light.

Language: Английский

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The PROTAC technology in drug development

Cell Biochemistry and Function, Journal Year: 2019, Volume and Issue: 37(1), P. 21 - 30

Published: Jan. 1, 2019

Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by molecule. This takes advantage of moiety targeted and recognizing E3 ubiquitin ligase produces hybrid molecule to specifically knock down protein. During first decade, three pedigreed groups worked on development this technology. To date, extended different groups, aiming develop drugs against diseases including cancers. review summarizes contributions PROTAC. Significance study summarized PROTAC readers also presented author's opinions application in tumor therapy.

Language: Английский

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