Name: ARD-69
Brand: BOC Sciences
Rating: 5 (1 reviews)

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Price

Stock

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$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Appearance

Solid Powder

Storage

Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)

IUPACName

(2S,4R)-N-((S)-3-(4-((4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

Synonyms

N-[(1-Fluorocyclopropyl)carbonyl]-3-methyl-L-valyl-(4R)-N-{(1S)-3-{4-[(4-{[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)ethynyl]-1,4'-bipiperidin-1'-yl}-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-3-oxopropyl}-4-hydroxy-L-prolinamide; L-Prolinamide, N-[(1-fluorocyclopropyl)carbonyl]-3-methyl-L-valyl-N-[(1S)-3-[4-[2-[4-[[[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]amino]carbonyl]phenyl]ethynyl][1,4'-bipiperidin]-1'-yl]-1-[4-(4-methyl-5-thiazolyl)phenyl]-3-oxopropyl]-4-hydroxy-, (4R)-; (2S,4R)-N-[(1S)-3-[4-[4-[2-[4-[[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl]ethynyl]piperidin-1-yl]piperidin-1-yl]-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-3-oxopropyl]-1-[(2S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide; ARD69; ARD 69

Density

1.34±0.1 g/cm3

InChI Key

CWGVEMFBQJUWLU-RXFAPWBBSA-N

InChI

InChI=1S/C62H74ClFN8O7S/c1-37-51(80-36-66-37)41-17-15-40(16-18-41)48(67-54(76)49-31-45(73)35-72(49)55(77)52(59(2,3)4)68-58(78)62(64)25-26-62)33-50(74)71-29-23-44(24-30-71)70-27-21-39(22-28-70)10-9-38-11-13-42(14-12-38)53(75)69-56-60(5,6)57(61(56,7)8)79-46-20-19-43(34-65)47(63)32-46/h11-20,32,36,39,44-45,48-49,52,56-57,73H,21-31,33,35H2,1-8H3,(H,67,76)(H,68,78)(H,69,75)/t45-,48+,49+,52-,56-,57-/m1/s1

SMILES

N#CC1=CC=C(OC2C(C)(C)C(NC(=O)C3=CC=C(C#CC4CCN(CC4)C5CCN(C(=O)CC(NC(=O)C6N(C(=O)C(NC(=O)C7(F)CC7)C(C)(C)C)CC(O)C6)C=8C=CC(=CC8)C=9SC=NC9C)CC5)C=C3)C2(C)C)C=C1Cl

Mechanism

Target: ARD-69 selectively targets androgen receptor in AR-positive prostate cancer models.

Binding site: Its AR ligand binds the androgen receptor ligand-binding domain.

Mechanism of action: ARD-69 is a potent androgen receptor PROTAC degrader designed to induce AR depletion through the ubiquitin-proteasome system. It combines an AR-binding ligand with an E3 ligase-recruiting moiety, enabling proximity-dependent ubiquitination and proteasomal degradation of AR protein in AR-positive cellular models. Reported studies show strong degradation activity in LNCaP, VCaP, and 22Rv1 cells, supporting its use for robust AR pathway interrogation. ARD-69 is useful for studying receptor turnover, AR-regulated gene-expression suppression, resistance-associated AR biology, and differences between receptor antagonism and targeted AR degradation.

Applications

• PROTAC-Mediated Degradation of Androgen Receptor: ARD-69 is designed to specifically target and degrade the androgen receptor, a critical player in prostate cancer progression. Utilizing the PROTAC mechanism, ARD-69 facilitates the ubiquitination and subsequent proteasomal degradation of the androgen receptor, offering a powerful tool for researchers examining androgen receptor biology and its role in cancer.

• Targeted Degradation in Drug Resistance Studies: ARD-69 enables the exploration of targeted protein degradation as a strategy to overcome drug resistance in cancer cells. By degrading the androgen receptor, researchers can investigate how cancer cells adapt to the absence of this protein, providing insights into resistance mechanisms and potential therapeutic interventions.

• PROTAC-Driven Selective Protein Knockdown: With ARD-69, researchers can achieve selective knockdown of the androgen receptor, allowing for the study of downstream signaling pathways and cellular processes affected by its absence. This application is crucial for dissecting the functional roles of the androgen receptor in various cellular contexts, beyond cancer.

• Mechanistic Studies of PROTAC Efficacy: ARD-69 serves as an excellent model compound for investigating the mechanistic aspects of PROTAC efficacy, including ligand binding, ubiquitination, and proteasomal engagement. These studies can enhance our understanding of PROTAC design principles and optimize future development of targeted degradation therapeutics.

1. Discovery of ARD-69 as a highly potent proteolysis targeting chimera (PROTAC) degrader of androgen receptor (AR) for the treatment of prostate cancer.

Han, X., Wang, C., Qin, C., Xiang, W., Fernandez-Salas, E., Yang, C.Y., Wang, M., Zhao, L., Xu, T., Chinnaswamy, K. and Delproposto, J., 2019. Journal of medicinal chemistry, 62(2), pp.941-964.

We report herein the discovery of highly potent PROTAC degraders of androgen receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate cancer.

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