ARN 509
[CAS# 956104-40-8]

Identification

• Classification: Biochemical >> Inhibitor >> Endocrinology & hormones >> Androgen receptor inhibitor
• Name: ARN 509
• Synonyms: 4-[7-[6-Cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide
• Molecular Formula: C₂₁H₁₅F₄N₅O₂S
• Molecular Weight: 477.44
• CAS Registry Number: 956104-40-8
• EC Number: 807-449-9
• SMILES: CNC(=O)C1=C(C=C(C=C1)N2C(=S)N(C(=O)C23CCC3)C4=CC(=C(N=C4)C#N)C(F)(F)F)F

Properties

• Solubility: Insoluble (1.3E^-3 g/L) (25 °C), Calc.^*, 15 mg/mL (DMSO), 5 mg/mL (ethanol) (Expl.)
• Density: 1.59±0.1 g/cm³ (20 °C 760 Torr), Calc.^*
• Index of Refraction: 1.659, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS08 Dander
• Risk Statements: H360
• Safety Statements: P203-P280-P318-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	1A	H360
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Reproductive toxicity	Repr.	2	H361
Reproductive toxicity	Repr.	1B	H360
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Skin sensitization	Skin Sens.	1B	H317
Acute toxicity	Acute Tox.	4	H302

Discovery and Applications

ARN 509 is a potent and selective androgen receptor (AR) antagonist, developed as a treatment for prostate cancer. It is a part of a new class of drugs known as AR signaling inhibitors, which target the androgen receptor pathway that plays a critical role in the progression of prostate cancer. Prostate cancer cells often depend on the androgen receptor for growth and survival, and the AR pathway is activated by androgens like testosterone. ARN 509 was designed to specifically inhibit this pathway, providing a targeted approach to treatment.

The discovery of ARN 509 is rooted in research into the mechanisms of androgen receptor signaling and the role androgens play in prostate cancer. In prostate cancer, particularly castration-resistant prostate cancer (CRPC), the disease becomes resistant to traditional androgen deprivation therapy (ADT). This resistance is partly due to mutations in the androgen receptor, which can result in a receptor that remains active even in the absence of androgens. ARN 509 was developed to overcome this resistance by binding to the androgen receptor and preventing its activation, even in the presence of androgens.

ARN 509 was initially developed by Aragon Pharmaceuticals and later acquired by Johnson & Johnson, which advanced its clinical development. The compound demonstrated strong preclinical activity and was tested in clinical trials for patients with prostate cancer. ARN 509 has been shown to be highly selective for the androgen receptor, which reduces the likelihood of off-target effects and enhances its potential for efficacy in prostate cancer treatment.

In clinical trials, ARN 509 has shown promise in treating metastatic castration-resistant prostate cancer (mCRPC), a stage of prostate cancer in which the disease continues to progress despite the reduction of androgen levels through ADT. Studies have demonstrated that ARN 509, when used alone or in combination with other therapies, significantly inhibits the growth of prostate cancer cells and improves progression-free survival in patients with mCRPC. As a selective androgen receptor inhibitor, ARN 509 offers a targeted approach that minimizes some of the side effects associated with conventional chemotherapy.

The clinical success of ARN 509 is part of a broader trend toward precision medicine in cancer treatment. By targeting specific molecular pathways like the androgen receptor, drugs such as ARN 509 provide a more focused and potentially more effective alternative to conventional chemotherapy, which can have widespread and often severe side effects. Furthermore, ARN 509 has potential for use in combination therapies, further enhancing its ability to treat patients with advanced prostate cancer.

Beyond prostate cancer, researchers are also investigating the potential of ARN 509 in treating other androgen receptor-driven conditions, such as breast cancer. Early studies suggest that ARN 509’s ability to modulate androgen receptor activity may have broader applications in oncology.

In summary, ARN 509 represents a significant advancement in the treatment of prostate cancer, particularly in overcoming the resistance mechanisms that limit the effectiveness of current therapies. As research continues, it is expected to play a key role in the management of advanced prostate cancer and potentially other androgen receptor-related diseases.

References

2010. Structure−Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC). Journal of Medicinal Chemistry, 53(7).
DOI: 10.1021/jm901488g

2024. Effect of concomitant medications on treatment response and survival in non-metastatic castrate resistant prostate cancer: Exploratory analysis of the SPARTAN trial. European Journal of Cancer, 208.
DOI: 10.1016/j.ejca.2024.114197

2024. Androgen receptor pathway inhibitors and drug-drug interactions in prostate cancer. ESMO Open, 9(11).
DOI: 10.1016/j.esmoop.2024.103736