Ruxolitinib
[CAS# 941678-49-5]

Identification

• Classification: Pharmaceutical intermediate >> API intermediate
• Name: Ruxolitinib
• Synonyms: INCB-018424; (betaR)-beta-Cyclopentyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1-propanenitrile
• Molecular Formula: C₁₇H₁₈N₆
• Molecular Weight: 306.36
• CAS Registry Number: 941678-49-5
• EC Number: 107-728-9
• SMILES: C1CCC(C1)[C@@H](CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3

Properties

• Solubility: 60 mg/mL (DMSO), <1 mg/mL (water), 60 mg/mL (ethanol) (Expl.)
• Density: 1.4±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.747, Calc.^*
• Boiling Point: 592.6±50.0 °C (760 mmHg), Calc.^*
• Flash Point: 312.2±30.1 °C, Calc.^*

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

Safety Data

• Hazard Symbols: GHS08 Warning
• Risk Statements: H361f-H373
• Safety Statements: P203-P260-P273-P280-P318-P319-P391-P405-P501

Discovery and Applications

Ruxolitinib is a selective inhibitor of Janus kinase (JAK) 1 and JAK2, enzymes that are involved in the signaling pathways of several cytokines and growth factors. The discovery of ruxolitinib stems from the understanding of the JAK-STAT signaling pathway, which plays a critical role in the regulation of immune response, cell growth, and hematopoiesis. In particular, mutations in JAK2 have been implicated in various hematologic conditions, including myeloproliferative neoplasms (MPNs). Ruxolitinib was developed to target these dysregulated JAK pathways and offer a therapeutic solution for diseases driven by aberrant JAK signaling.

Ruxolitinib was first approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of intermediate or high-risk myelofibrosis, a type of MPN. Myelofibrosis is characterized by the scarring of bone marrow, which disrupts normal blood cell production. Patients with this condition often experience symptoms such as fatigue, spleen enlargement (splenomegaly), and anemia. Ruxolitinib works by inhibiting the JAK2 mutation that leads to excessive cell production and splenomegaly. By inhibiting the overactive JAK2 signaling, ruxolitinib helps reduce the size of the spleen and alleviates symptoms, improving the overall quality of life for patients with myelofibrosis.

In addition to myelofibrosis, ruxolitinib is approved for the treatment of polycythemia vera (PV), another MPN characterized by an overproduction of red blood cells. In PV, the overactive JAK2 signaling causes the uncontrolled proliferation of hematopoietic cells. Ruxolitinib helps control this excessive production of blood cells and improves the symptoms associated with PV, such as itching and fatigue. Its use in PV was approved by the FDA in 2014 after clinical studies demonstrated its effectiveness in reducing hematocrit levels and alleviating disease-related symptoms.

The discovery and development of ruxolitinib have had a significant impact on the treatment of hematologic diseases associated with JAK2 mutations. Prior to the introduction of ruxolitinib, patients with myelofibrosis and polycythemia vera had limited therapeutic options. Ruxolitinib has proven to be effective in managing symptoms and improving survival in these patient populations. Its ability to target JAK2 specifically offers a more targeted and effective treatment compared to traditional therapies that may not address the underlying genetic mutations driving these diseases.

Beyond its approved indications, ruxolitinib is being studied for potential use in other autoimmune and inflammatory conditions. Research is ongoing to explore its application in diseases such as rheumatoid arthritis, psoriasis, and graft-versus-host disease (GVHD), where JAK1 and JAK2 play a central role in the inflammatory response.

Ruxolitinib represents a milestone in targeted therapy, offering a more precise approach to treating diseases with underlying JAK-STAT pathway dysregulation. Its discovery and application continue to advance the treatment of myeloproliferative neoplasms and other conditions associated with abnormal JAK signaling.

References

2013. Tumoricidal effects of the JAK inhibitor Ruxolitinib (INC424) on hepatocellular carcinoma in vitro. Cancer Letters, 341(2).
DOI: 10.1016/j.canlet.2013.08.009

2017. Ruxolitinib for essential thrombocythemia refractory to or intolerant of hydroxyurea: long-term phase 2 study results. Blood, 130(15).
DOI: 10.1182/blood-2017-02-765032

2024. Treatment of steroid-refractory acute/chronic graft versus host disease: A single-center real-world experience of ruxolitinib in combination with extracorporeal photopheresis in a high-risk population. Leukemia Research, 147.
DOI: 10.1016/j.leukres.2024.107611