Name: ACBI1
Brand: BOC Sciences
Rating: 5 (1 reviews)

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$--

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Solubility

10 mM in DMSO;H2O : ≥ 150 mg/mL

Storage

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

Shipping

Room temperature in continental US; may vary elsewhere

IUPACName

(2S,4R)-N-[[2-[2-[4-[[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]piperazin-1-yl]methyl]phenoxy]ethoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide

Synonyms

ACBI 1; ACBI-1; (2S,4R)-N-(2-(2-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)methyl)phenoxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

Boiling Point

1144.1±65.0°C at 760 Torr

Density

1.41±0.1 g/cm3

InChI Key

IVARZBJJMMUJHI-SQKKEFIPSA-N

InChI

InChI=1S/C49H58FN9O7S/c1-30-42(67-29-53-30)32-11-12-33(26-52-45(62)39-24-34(60)28-59(39)46(63)43(48(2,3)4)54-47(64)49(50)15-16-49)41(23-32)66-22-21-65-35-13-9-31(10-14-35)27-57-17-19-58(20-18-57)38-25-37(55-56-44(38)51)36-7-5-6-8-40(36)61/h5-14,23,25,29,34,39,43,60-61H,15-22,24,26-28H2,1-4H3,(H2,51,56)(H,52,62)(H,54,64)/t34-,39+,43-/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)OCCOC5=CC=C(C=C5)CN6CCN(CC6)C7=CC(=NN=C7N)C8=CC=CC=C8O

Mechanism

Target: Targets SMARCA2, SMARCA4, and PBRM1 bromodomain-containing BAF proteins for experimental targeted protein degradation studies.

Binding Site: Binds the BAF bromodomain acetyl-lysine pocket and VHL substrate-recognition domain to support productive ternary complex formation.

Mechanism of Action: ACBI1 is designed for use in PROTAC or targeted protein degradation experiments directed toward SMARCA2, SMARCA4, and PBRM1 bromodomain-containing BAF proteins. The bifunctional molecule links a target-recognition element to VHL, promoting proximity between the protein of interest and ubiquitination machinery. Productive ternary-complex formation can drive polyubiquitination and proteasome-dependent target depletion, allowing researchers to compare pharmacological inhibition with protein removal. It is suitable for evaluating degradation potency, kinetics, pathway selectivity, and downstream signaling consequences in engineered or disease-relevant cellular models.

Applications

• PROTAC-Mediated Protein Degradation: ACBI1 is utilized to facilitate the selective degradation of target proteins, allowing researchers to study protein function and regulation through the precise removal of specific proteins in cellular systems. This approach aids in dissecting complex biological pathways and understanding the roles of proteins in various disease models.

• Targeted Degradation in Oncology: Researchers employ ACBI1 to investigate cancer-related proteins by inducing their degradation. This application helps elucidate the mechanisms of oncogenesis and identify potential therapeutic targets, advancing the development of novel cancer treatment strategies through the modulation of protein levels.

• Mechanistic Studies of E3 Ligases: By using ACBI1, scientists can explore the interactions between target proteins and E3 ligases, providing insights into the ubiquitin-proteasome system. This research direction enhances the understanding of protein homeostasis and the implications of E3 ligase activity in cellular processes.

• Functional Genomics with PROTACs: ACBI1 serves as a tool in functional genomics studies, enabling the systematic degradation of proteins to assess their roles in gene expression and cellular phenotypes. This application supports the identification of key regulatory proteins and the mapping of genetic networks.

1. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.

Farnaby, W., Koegl, M., Roy, M.J., Whitworth, C., Diers, E., Trainor, N., Zollman, D., Steurer, S., Karolyi-Oezguer, J., Riedmueller, C. and Gmaschitz, T., 2019. Nature chemical biology, 15(7), pp.672-680.

Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.

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