Name: ARD-266
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

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-[(1S)-3-[4-[2-[4-[[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl]ethynyl]piperidin-1-yl]-3-oxo-1-phenylpropyl]-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide

Synonyms

2-Pyrrolidinecarboxamide, N-[(1S)-3-[4-[2-[4-[[[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]amino]carbonyl]phenyl]ethynyl]-1-piperidinyl]-3-oxo-1-phenylpropyl]-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-5-isoxazolyl)-1-oxobutyl]-, (2S,4R)-; (2S,4R)-N-((S)-3-(4-((4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)ethynyl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide; (2S,4R)-N-[(1S)-3-[4-[2-[4-[[[trans-3-(3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]amino]carbonyl]phenyl]ethynyl]-1-piperidinyl]-3-oxo-1-phenylpropyl]-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-5-isoxazolyl)-1-oxobutyl]-2-pyrrolidinecarboxamide

Boiling Point

1095.6±65.0°C at 760 Torr

Density

1.31±0.1 g/cm3

InChI Key

RTNONCBKGZNCJS-LJLQSONVSA-N

InChI

InChI=1S/C52H59ClN6O7/c1-31(2)45(43-25-32(3)57-66-43)48(64)59-30-38(60)26-42(59)47(63)55-41(35-11-9-8-10-12-35)28-44(61)58-23-21-34(22-24-58)14-13-33-15-17-36(18-16-33)46(62)56-49-51(4,5)50(52(49,6)7)65-39-20-19-37(29-54)40(53)27-39/h8-12,15-20,25,27,31,34,38,41-42,45,49-50,60H,21-24,26,28,30H2,1-7H3,(H,55,63)(H,56,62)/t38-,41+,42+,45-,49-,50-/m1/s1

SMILES

N#CC1=CC=C(OC2C(C)(C)C(NC(=O)C3=CC=C(C#CC4CCN(C(=O)CC(NC(=O)C5N(C(=O)C(C=6ON=C(C6)C)C(C)C)CC(O)C5)C=7C=CC=CC7)CC4)C=C3)C2(C)C)C=C1Cl

Mechanism

Target: ARD-266 selectively targets androgen receptor in AR-positive cellular systems.

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

Mechanism of action: ARD-266 is a highly potent VHL-recruiting androgen receptor PROTAC designed to induce rapid AR protein degradation. The molecule links an AR-recognition ligand to a von Hippel-Lindau ligand, enabling formation of AR–PROTAC–VHL ternary complexes and subsequent ubiquitination of AR. Proteasome-mediated receptor depletion suppresses AR-regulated transcriptional outputs such as PSA, TMPRSS2, and FKBP5 in AR-positive models. ARD-266 is useful for studying receptor turnover, AR transcriptional dependency, degradation potency, resistance-associated receptor biology, and differences between ligand-domain antagonism and complete AR protein depletion.

Applications

• PROTAC-Mediated Cancer Research: ARD-266 is utilized in studying the degradation of oncogenic proteins, providing a novel approach for cancer research by selectively eliminating proteins involved in tumor growth and survival, thereby offering insights into potential therapeutic strategies.

• Targeted Protein Degradation in Neurodegenerative Diseases: ARD-266 facilitates the degradation of proteins implicated in neurodegenerative disorders, enabling researchers to investigate the therapeutic potential of reducing toxic protein aggregates in diseases such as Alzheimer's and Parkinson's.

• Investigating Protein-Protein Interactions: By employing ARD-266, researchers can study the dynamic interactions of protein complexes through targeted degradation, allowing for the elucidation of complex biological pathways and the identification of novel therapeutic targets.

• Advancing Chemical Biology: ARD-266 serves as a tool in chemical biology to explore the mechanistic aspects of PROTAC technology, aiding in the development of next-generation degraders with improved specificity and efficacy for various protein targets.

1. Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands

Lijie Zhao, Jeanne Stuckey, Weiguo Xiang, Krishnapriya Chinnaswamy, Xin Han, Shaomeng Wang, Mi Wang, Bukeyan Miao, Chao-Yie Yang, Tianfeng Xu, Chong Qin J Med Chem . 2019 Dec 26;62(24):11218-11231. doi: 10.1021/acs.jmedchem.9b01393.

Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization of highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using a potent AR antagonist and E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in the discovery of11(ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC50values of 0.2-1 nM. ARD-266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression. For the first time, we demonstrated that an E3 ligand with micromolar binding affinity to its E3 ligase complex can be successfully employed for the design of highly potent and efficient PROTAC degraders and this finding may have a significant implication for the field of PROTAC research.

Stock concentration: *

Desired final volume: *

Desired concentration: *

* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂