Belzutifan
[CAS# 1672668-24-4]

Identification

• Classification: Organic raw materials >> Organic fluorine compound >> Fluorobenzonitrile series
• Name: Belzutifan
• Synonyms: 3-[[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]oxy]-5-fluorobenzonitrile
• Molecular Formula: C₁₇H₁₂F₃NO₄S
• Molecular Weight: 383.34
• CAS Registry Number: 1672668-24-4
• EC Number: 849-064-9
• SMILES: CS(=O)(=O)C1=C2[C@@H]([C@@H]([C@@H](C2=C(C=C1)OC3=CC(=CC(=C3)C#N)F)F)F)O

Properties

• Density: 1.6±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.610, Calc.^*
• Boiling Point: 505.8±50.0 °C (760 mmHg), Calc.^*
• Flash Point: 259.7±30.1 °C, Calc.^*

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

Safety Data

• Hazard Symbols: GHS08;GHS09 Warning
• Risk Statements: H361d-H373-H411
• Safety Statements: P203-P260-P273-P280-P318-P319-P391-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Reproductive toxicity	Repr.	2	H361fd

Discovery and Applications

Belzutifan is a small-molecule inhibitor that targets hypoxia-inducible factor 2-alpha (HIF-2α), a transcription factor implicated in the progression of clear cell renal cell carcinoma (ccRCC) and other cancers. The discovery of Belzutifan stemmed from efforts to address von Hippel-Lindau (VHL) disease-associated tumors, which are driven by aberrant HIF signaling. By selectively inhibiting HIF-2α, Belzutifan disrupts pathways promoting angiogenesis, cell proliferation, and survival under hypoxic conditions.

The synthesis of Belzutifan involves a series of strategic modifications to enhance selectivity and bioavailability, optimizing the interaction with HIF-2α. This process includes structure-guided design techniques that refine the molecular framework to maximize efficacy and minimize off-target effects. Key intermediates are synthesized through nucleophilic substitutions and cyclization reactions, ultimately yielding the bioactive inhibitor.

Clinically, Belzutifan has demonstrated significant promise in treating VHL disease-associated renal cell carcinoma, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors. Its approval marked a milestone as the first FDA-approved HIF-2α inhibitor, highlighting its role as a pioneering agent in targeted cancer therapy. Ongoing research aims to expand its application to other solid tumors driven by hypoxic signaling.

The development of Belzutifan underscores the importance of targeting transcription factors in cancer treatment. As further studies explore combination therapies and new indications, Belzutifan continues to shape the landscape of oncology drug discovery.

References

2023. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. Lancet Oncology, 24(4).
DOI: 10.1016/s1470-2045(23)00123-7

2024. Advances in the management of von Hippel-Lindau disease-associated renal cell carcinoma. Journal of Clinical Neuroscience, 120.
DOI: 10.1016/j.jocn.2024.110774

2021. Discovery of belzutifan (MK-6482) as a potent and selective HIF2α inhibitor for the treatment of clear cell renal cell carcinoma (ccRCC). Journal of Medicinal Chemistry, 64(14).
DOI: 10.1021/acs.jmedchem.0c01901