442633-00-3

Basic information

• Product Name: 2-Fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide
• Synonyms: 2-Fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide;CK 666;CK-0944666;Arp2/3 Complex Inhibitor I, CK-666
• CAS NO: 442633-00-3
• Molecular Formula: C₁₈H₁₇FN₂O
• Molecular Weight: 296
• Mol File: 442633-00-3.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 528.2±50.0 °C(Predicted)
• Appearance: white to tan/
• Density: 1.235±0.06 g/cm3(Predicted)
• Storage Temp.: Store at -20°C
• Solubility: DMSO: ≥25mg/mL
• PKA: 13.86±0.46(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: 2-Fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide(442633-00-3)
• EPA Substance Registry System: 2-Fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide(442633-00-3)

Safety Data

• Hazard Codes: Xi
• Statements: 36
• Safety Statements: 26
• WGK Germany: 3
• Hazardous Substances Data: 442633-00-3(Hazardous Substances Data)

Usage

Description

2-Fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide, also known as CK-666, is a potent, selective, and reversible inhibitor of the ARP2/3 complex (actin-related proteins 2 and 3) with an IC50 of 4 μM for human ARP2/3. It blocks actin nucleation and significantly alters lamellipodial actin architecture, suspended cell shape, and the cell spreading process. CK-666 is an important new tool for studying actin assembly and the diverse range of actin-related processes in normal and pathophysiological conditions.

Uses

Used in Research Applications:
2-Fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide is used as a research tool for studying Arp2/3-mediated structural changes in cells. It helps researchers understand the role of ARP2/3 complex in various cellular processes and its potential as a therapeutic target for various diseases.
Used in Pharmaceutical Industry:
2-Fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide is used as a potential therapeutic agent for the treatment of diseases associated with actin dysregulation. Its ability to inhibit the ARP2/3 complex makes it a promising candidate for the development of drugs targeting actin-related disorders.
Used in Neuroscience Research:
2-Fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide is used in neuroscience research to study the role of actin dynamics in brain function and neurological disorders. It helps researchers investigate the impact of actin regulation on synaptic plasticity, neuronal connectivity, and the progression of neurodegenerative diseases.
Used in Drug Discovery:
2-Fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide is used in drug discovery to identify new compounds that can modulate the activity of the ARP2/3 complex. This can lead to the development of novel therapeutic agents for the treatment of various diseases, including cancer, autoimmune disorders, and infectious diseases.

Biochem/physiol Actions

CK-666 binds to Arp2/3 complex, stabilizes the inactive state of the complex and prevents its movement into active conformation.

References

1) Nolan et al. (2009), Characterization of two classes of small molecule inhibitors of Arp2/3 complex; Nature, 460 1031 2) Henson et al. (2015), Arp2/3 complex inhibition radically alters lamellipodial actin architecture, suspended cell shape, and the cell spreading process; Mol. Biol. Cell, 26 887 3) Park et al. (2013), Methamphetamine-induced occluding endocytosis is mediated by the Arp2/3 complex-regulated actin rearrangement; J. Biol. Chem., 288 33324 4) Sun et al. (2013), Actin nucleator Arp2/3 complex is essential for mouse preimplantation embryo development; Reprod. Fertil. Dev., 25 617 5) Efremov et al. (2015), Distinct impact of targeted actin cytoskeleton reorganization on mechanical properties of normal and malignant cells; Biochim. Biophys. Acta, 1853 (11PtB) 3117

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Relevant articles and documents

Structural Characterization and Computer-Aided Optimization of a Small-Molecule Inhibitor of the Arp2/3 Complex, a Key Regulator of the Actin Cytoskeleton

CK-666 (1) is a recently discovered small-molecule inhibitor of the actin-related protein 2/3 (Arp2/3) complex, a key actin cytoskeleton regulator with roles in bacterial pathogenesis and cancer cell motility. Although 1 is commercially available, the crystal structure of Arp2/3 complex with 1 bound has not been reported, making its mechanism of action uncertain. Furthermore, its relatively low potency increases its potential for off-target effects invivo, complicating interpretation of its influence in cell biological studies and precluding its clinical use. Herein we report the crystal structure of 1 bound to Arp2/3 complex, which reveals that 1 binds between the Arp2 and Arp3 subunits to stabilize the inactive conformation of the complex. Based on the crystal structure, we used computational docking and free-energy perturbation calculations of monosubstituted derivatives of 1 to guide optimization efforts. Biochemical assays of ten newly synthesized compounds led to the identification of compound 2, which exhibits a threefold increase in inhibitory activity invitro relative to 1. In addition, our computational analyses unveiled a surface groove at the interface of the Arp2 and Arp3 subunits that can be exploited for additional structure-based optimization.