MDV 3100
[CAS# 915087-33-1]

Identification

• Classification: Biochemical >> Inhibitor >> Endocrinology & hormones >> Androgen receptor antagonist
• Name: MDV 3100
• Synonyms: 4-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methylbenzamide
• Molecular Formula: C₂₁H₁₆F₄N₄O₂S
• Molecular Weight: 464.44
• CAS Registry Number: 915087-33-1
• EC Number: 805-022-1
• SMILES: CC1(C(=O)N(C(=S)N1C2=CC(=C(C=C2)C(=O)NC)F)C3=CC(=C(C=C3)C#N)C(F)(F)F)C

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Index of refraction: 1.63 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07;GHS08;GHS09 Danger
• Risk Statements: H302-H360-H361-H372-H373-H411
• Safety Statements: P203-P260-P264-P270-P273-P280-P301+P317-P318-P319-P330-P391-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Reproductive toxicity	Repr.	1B	H360
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Reproductive toxicity	Repr.	2	H361
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Reproductive toxicity	Repr.	1B	H360D
Carcinogenicity	Carc.	2	H351

Discovery and Applications

MDV3100, known generically as enzalutamide, is a synthetic non-steroidal antiandrogen that was developed as a treatment for prostate cancer. It was originally discovered by researchers at the University of California, Los Angeles (UCLA) and later licensed to Medivation, Inc., a biopharmaceutical company. The compound gained the designation MDV3100 during its development phase, and following successful clinical trials, it was approved for medical use under the trade name Xtandi. The therapeutic innovation it represents lies in its ability to overcome resistance to earlier-generation antiandrogens used in prostate cancer therapy.

The discovery of MDV3100 was driven by the clinical challenge of castration-resistant prostate cancer (CRPC), a form of the disease that continues to progress despite androgen deprivation therapy. Traditional antiandrogens such as bicalutamide were often rendered ineffective as prostate cancer cells developed mechanisms to bypass androgen blockade, including overexpression or mutation of the androgen receptor (AR). MDV3100 was designed specifically to address these limitations by more effectively targeting the androgen receptor signaling pathway.

Mechanistically, MDV3100 functions as a high-affinity androgen receptor inhibitor. It binds competitively to the ligand-binding domain of the receptor, preventing the activation by androgens such as testosterone and dihydrotestosterone. Unlike earlier antiandrogens, MDV3100 not only inhibits AR binding but also impairs its nuclear translocation and DNA binding, thereby effectively blocking the transcription of AR-regulated genes that promote tumor growth. Furthermore, MDV3100 does not exhibit partial agonist activity, which was a known drawback of older antiandrogens, making it more effective in treating advanced prostate cancer.

The application of MDV3100 has been validated in clinical settings. It demonstrated significant improvement in overall survival and progression-free survival in patients with metastatic CRPC, including those who had previously undergone chemotherapy with docetaxel. Its approval by regulatory agencies such as the U.S. Food and Drug Administration (FDA) marked a major advancement in prostate cancer treatment, providing an oral therapeutic option with a favorable efficacy and safety profile.

Following its approval, enzalutamide has been widely adopted in clinical oncology. It is administered orally and is typically used in combination with ongoing androgen deprivation therapy. The success of MDV3100 has also prompted further research into its use in earlier stages of prostate cancer, including non-metastatic CRPC and hormone-sensitive prostate cancer, where it has shown benefit in delaying disease progression.

Beyond its primary indication, MDV3100 has been investigated in combination with other therapeutic agents such as abiraterone acetate, chemotherapy, and immune checkpoint inhibitors. However, combination regimens must be carefully evaluated due to the potential for overlapping toxicities or pharmacokinetic interactions. Enzalutamide is known to have certain side effects, including fatigue, hypertension, and an increased risk of seizures, which are attributed to its ability to cross the blood-brain barrier and affect central nervous system function.

The development and clinical deployment of MDV3100 represent a paradigm shift in the management of advanced prostate cancer. It exemplifies rational drug design based on molecular understanding of disease resistance mechanisms and has laid the groundwork for the next generation of androgen receptor signaling inhibitors. Subsequent drug development efforts have focused on creating analogues with improved potency, pharmacokinetics, and safety profiles.

In conclusion, MDV3100 has become a cornerstone in the treatment of prostate cancer, particularly in patients with castration-resistant disease. Its mechanism of action, clinical efficacy, and broad application in oncological practice underscore its importance as a therapeutic milestone. Continued research into AR-targeted therapies is likely to build on the foundation established by MDV3100, further enhancing outcomes for patients with prostate cancer.

References

2012. ARN-509: A Novel Antiandrogen for Prostate Cancer Treatment. Cancer Research, 72(6).
DOI: 10.1158/0008-5472.can-11-3948

2016. Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer. European Journal of Medicinal Chemistry, 121.
DOI: 10.1016/j.ejmech.2016.04.052

2017. Androgen-deprivation therapy with enzalutamide enhances prostate cancer metastasis via decreasing the EPHB6 suppressor expression. Cancer Letters, 408.
DOI: 10.1016/j.canlet.2017.08.014