Name: VZ185
Brand: BOC Sciences
Rating: 5 (1 reviews)

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$--

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Solubility

10 mM in DMSO

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

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Room temperature in continental US; may vary elsewhere

Synonyms

VZ185; VZ-185; VZ 185; (2S,4R)-N-[[2-[5-[4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl]pentoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide

InChI Key

ZAGCLFXBHOXXEN-JPTLTNPLSA-N

InChI

InChI=1S/C53H67FN8O8S/c1-33-46(71-32-57-33)34-11-12-35(27-56-48(64)42-26-37(63)29-62(42)50(66)47(52(2,3)4)58-51(67)53(54)14-15-53)43(23-34)70-22-10-8-9-17-60-18-20-61(21-19-60)31-41-44(68-6)24-36(25-45(41)69-7)40-30-59(5)49(65)39-28-55-16-13-38(39)40/h11-13,16,23-25,28,30,32,37,42,47,63H,8-10,14-15,17-22,26-27,29,31H2,1-7H3,(H,56,64)(H,58,67)/t37-,42+,47-/m1/s1

SMILES

CC1=C(SC=N1)C2=CC(=C(C=C2)CNC(=O)C3CC(CN3C(=O)C(C(C)(C)C)NC(=O)C4(CC4)F)O)OCCCCCN5CCN(CC5)CC6=C(C=C(C=C6OC)C7=CN(C(=O)C8=C7C=CN=C8)C)OC

Mechanism

Target: VZ185 selectively targets bromodomain-containing proteins BRD9 and BRD7 for degradation.

Binding site: It binds the acetyl-lysine recognition pockets of BRD9 and BRD7 bromodomains.

Mechanism of action: VZ185 is a potent VHL-based dual degrader probe for BRD9 and BRD7. The compound links a bromodomain-recognition ligand to a von Hippel-Lindau E3 ligase ligand, inducing ternary-complex formation that enables ubiquitination and rapid proteasomal degradation of both targets. Because BRD9 and BRD7 participate in chromatin-associated regulatory complexes, VZ185 provides a valuable tool for studying SWI/SNF-related bromodomain biology, target redundancy, and transcriptional effects of bromodomain protein depletion. Its paired inactive or control analogs can support interpretation of degradation-dependent cellular phenotypes.

Applications

• PROTAC-Mediated Kinase Degradation: VZ185 is instrumental in the targeted degradation of specific kinases, providing a valuable tool for researchers studying kinase signaling pathways. By facilitating the removal of these proteins, VZ185 aids in dissecting their roles in cellular processes and disease mechanisms, offering deeper insights into kinase-mediated regulation.

• Targeted Protein Degradation in Cancer Research: Utilizing VZ185 in cancer research enables the selective degradation of oncogenic proteins, offering a novel approach to investigate tumorigenesis. This PROTAC compound helps elucidate the functional consequences of degrading cancer-related proteins, advancing our understanding of potential therapeutic targets in oncology.

• Mechanistic Studies of Protein-Protein Interactions: VZ185 serves as a powerful tool in studying protein-protein interactions through targeted degradation. By selectively degrading one component of a protein complex, researchers can analyze the resulting effects on cellular pathways, providing insights into the dynamic nature of protein interactions and their biological significance.

• Drug Resistance Mechanism Exploration: Employing VZ185 in drug resistance studies allows for the targeted degradation of proteins implicated in resistance pathways. This application aids researchers in identifying and validating new targets for overcoming resistance, thereby enhancing the development of more effective therapeutic strategies.

1. 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

Vittoria Zoppi, Scott J Hughes, Chiara Maniaci, Andrea Testa, Teresa Gmaschitz, Corinna Wieshofer, Manfred Koegl, Kristin M Riching, Danette L Daniels, Andrea Spallarossa, Alessio Ciulli J Med Chem. 2019 Jan 24;62(2):699-726. doi: 10.1021/acs.jmedchem.8b01413.Epub 2018 Dec 28.

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

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Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂