Ruxolitinib Phosphate
[CAS# 1092939-17-7]

Identification

• Classification: Pharmaceutical intermediate >> API intermediate
• Name: Ruxolitinib Phosphate
• Synonyms: INCB 018424; (betaR)-beta-Cyclopentyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1-propanenitrile phosphate
• Molecular Formula: C₁₇H₁₈N₆.H₃PO₄
• Molecular Weight: 404.36
• CAS Registry Number: 1092939-17-7
• EC Number: 641-390-8
• SMILES: C1CCC(C1)[C@@H](CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3.OP(=O)(O)O

Safety Data

• Hazard Symbols: GHS06;GHS07;GHS08 Danger
• Risk Statements: H301-H302-H361-H373-H412
• Safety Statements: P203-P260-P264-P270-P273-P280-P301+P316-P301+P317-P318-P319-P321-P330-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Reproductive toxicity	Repr.	2	H361
Acute toxicity	Acute Tox.	4	H302
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412

Discovery and Applications

Ruxolitinib phosphate is the phosphate salt form of ruxolitinib, a small-molecule inhibitor that selectively targets Janus-associated kinases (JAK1 and JAK2). It is used as an orally administered pharmaceutical agent for the treatment of several hematologic and inflammatory disorders. The compound is classified as a kinase inhibitor and functions by interrupting the JAK-STAT signaling pathway, which is crucial in mediating immune responses and hematopoiesis.

Ruxolitinib itself was developed through medicinal chemistry efforts to design selective inhibitors of JAK enzymes, particularly JAK2, which is implicated in the pathogenesis of myeloproliferative neoplasms (MPNs). Following extensive screening and optimization, ruxolitinib was identified as a potent and selective ATP-competitive inhibitor of JAK1 and JAK2. Its phosphate salt form, ruxolitinib phosphate, enhances aqueous solubility and is the form used in clinical formulations.

The discovery and development of ruxolitinib phosphate were closely tied to research into the genetic mutations associated with primary myelofibrosis and related conditions. In particular, the identification of the JAK2 V617F mutation in patients with MPNs provided a molecular target for drug development. Ruxolitinib phosphate was developed to address this target and was later approved based on clinical trials demonstrating efficacy in reducing splenomegaly and alleviating constitutional symptoms in patients with myelofibrosis.

Ruxolitinib phosphate was approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. It was later approved for additional indications, including polycythemia vera in patients who are resistant or intolerant to hydroxyurea, and steroid-refractory acute graft-versus-host disease (GVHD) in both adults and children aged 12 years and older.

The therapeutic effects of ruxolitinib phosphate are achieved through the inhibition of JAK1 and JAK2-mediated phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins. By suppressing this pathway, the drug reduces cytokine-driven proliferation and inflammation, leading to improved clinical outcomes in diseases characterized by dysregulated JAK-STAT signaling.

Ruxolitinib phosphate is administered orally, and its pharmacokinetics are characterized by rapid absorption and extensive hepatic metabolism, primarily via the cytochrome P450 enzyme CYP3A4. The drug has a relatively short half-life, necessitating twice-daily dosing in most therapeutic settings.

The compound has also been investigated for off-label and emerging indications, including other inflammatory or autoimmune diseases. However, such uses are subject to ongoing clinical evaluation and regulatory assessment.

In clinical practice, ruxolitinib phosphate is generally well tolerated, though it may cause side effects such as anemia, thrombocytopenia, and increased risk of infections due to its immunomodulatory effects. As a result, patients undergoing treatment are closely monitored through regular blood tests and clinical assessments.

In summary, ruxolitinib phosphate is a targeted JAK1/2 inhibitor developed for the treatment of myeloproliferative neoplasms and related conditions. Its discovery was driven by advances in understanding the molecular basis of hematologic diseases, and its application represents a significant advancement in the management of disorders involving dysregulated cytokine signaling.

References

2012. JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths. Blood, 119(12).
DOI: 10.1182/blood-2011-11-395228

2014. Remission of Recalcitrant Dermatomyositis Treated with Ruxolitinib. The New England Journal of Medicine, 371(26).
DOI: 10.1056/nejmc1412997

2020. Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia. Journal of Clinical Oncology, 38(10).
DOI: 10.1200/jco.19.00895