Article
Chemistry, Medicinal
Anniina T. Virtanen, Teemu Haikarainen, Parthasarathy Sampathkumar, Maaria Palmroth, Sanna Liukkonen, Jianping Liu, Natalia Nekhotiaeva, Stevan R. Hubbard, Olli Silvennoinen
Summary: This study identified novel small molecules targeting the JH2 domain of JAK2 V617F and characterized their binding properties. Screening of a large number of small molecules resulted in the identification of 55 binders to the ATP-binding pocket of JAK2 JH2 V617F protein. These findings reveal the unique structural characteristics of the JAK2 JH2 ATP-binding pocket.
Article
Medicine, General & Internal
Hengwei Wu, Jimin Shi, Yi Luo, Yamin Tan, Mingming Zhang, Xiaoyu Lai, Jian Yu, Lizhen Liu, Huarui Fu, He Huang, Yanmin Zhao
Summary: In this study, the clinical response to ruxolitinib in patients with steroid-refractory chronic graft-vs-host disease after allogeneic hematopoietic stem cell transplantation was investigated, and its safety profile was evaluated during the treatment course. The majority of patients treated with ruxolitinib showed significant treatment responses with a relatively well-tolerated safety profile, with lung involvement and matched related donors being associated with less favorable treatment response.
Review
Oncology
Srdan Verstovsek, Ruben A. Mesa, Robert A. Livingston, Wilson Hu, John Mascarenhas
Summary: Myelofibrosis is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been approved for the treatment of intermediate or high-risk MF patients. It remains the standard of care for higher-risk MF, and dose optimization and management are crucial for maximizing its benefits.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2023)
Article
Microbiology
Lin Du, Yolanda Wong Ying Yip, Him Kwan Ng, Bo Man Ho, Jing-Na He, Sun On Chan, Chi Pui Pang, Wai Kit Chu
Summary: Uveitis is an inflammatory disease of intraocular structures associated with Reiter's syndrome, often treated with corticosteroids but needing non-steroidal treatments due to side effects. Research shows that the JAK inhibitor ruxolitinib can alleviate endotoxin-induced uveitis and rescue visual functions in rats by inhibiting the JAK2-STAT3 pathway.
Article
Biochemistry & Molecular Biology
Maxim Kondratyev, Vladimir R. Rudnev, Kirill S. Nikolsky, Alexander A. Stepanov, Denis Petrovsky, Liudmila Kulikova, Arthur T. Kopylov, Kristina A. Malsagova, Anna L. Kaysheva
Summary: Rheumatoid arthritis is a chronic autoimmune disease characterized by destructive synovitis and extra-articular manifestations. Cytokines play a role in the pathogenesis of rheumatoid arthritis by regulating inflammatory processes and inducing autoimmunity and chronic inflammation. Janus-associated kinase (JAK) and signal transducer and activator of transcription (STAT) proteins are involved in the development of autoimmune and inflammatory diseases. Small-molecule drugs that target JAK proteins are used for the treatment of rheumatoid arthritis. In this study, we investigated the interactions between the small-molecule drug ruxolitinib and JAK1 and JAK2 isoforms using molecular docking. Our results show that ruxolitinib selectively binds to JAK1 and JAK2 isoforms with high affinity, primarily through hydrophobic interactions. The specific amino acid residues responsible for the binding and retention of ruxolitinib were identified.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, General & Internal
Yotaro Tamai, Shinichi Teshima, Shun Tsunoda, Wataru Kamata, Shuku Sato
Summary: This case report describes a patient with MPN complicated by alopecia areata. The patient presented with mild platelet elevation, fatigue, and hot flashes. Genetic testing confirmed the presence of the JAK2 V617F mutation, supporting the diagnosis of MPN, unclassifiable. Treatment with ruxolitinib led to significant hair growth improvement in the patient.
FRONTIERS IN MEDICINE
(2022)
Article
Pharmacology & Pharmacy
James T. England, Vikas Gupta
Summary: Ruxolitinib is commonly used for MF patients, but its response durability is limited. Long-term data for fedratinib and pacritinib are not available. This review examines the data, outlines the role of fedratinib in MF treatment, and highlights the knowledge gaps for optimizing its use.
EXPERT OPINION ON PHARMACOTHERAPY
(2022)
Article
Hematology
Justin Anthony Chen, Yanli Hou, Krishna M. Roskin, Daniel A. Arber, Charles D. Bangs, Linda B. Baughn, Athena M. Cherry, Mark D. Ewalt, Andrew Z. Fire, Laure Fresard, Hutton M. Kearney, Stephen B. Montgomery, Robert S. Ohgami, Kathryn E. Pearce, Beth A. Pitel, Jason D. Merker, Jason Gotlib
Summary: The resistance mechanisms to ruxolitinib in a patient with JAK2-driven hematologic malignancies may involve IKZF1 deletion and an activated B-cell receptor-like signaling phenotype.
Review
Pharmacology & Pharmacy
Douglas Tremblay, John Mascarenhas
Summary: Myelofibrosis is a hematologic malignancy characterized by splenomegaly in 80% of newly diagnosed patients. JAK inhibitors are the main pharmacologic treatment for splenomegaly, but their efficacy in reducing spleen size is variable and the duration of benefit is limited.
EXPERT OPINION ON PHARMACOTHERAPY
(2023)
Review
Biochemistry & Molecular Biology
Ruchi Yadav, Narek Hakobyan, Jen-Chin Wang
Summary: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are enduring and well-known conditions characterized by abnormal growth of hematopoietic cell lineages, chronic inflammation, and dysregulated immune system. Immune checkpoint inhibitor therapy (ICIT) has shown impressive clinical success but faces challenges of tumor resistance. Next-generation ICIT targeting new immune checkpoints in the tumor microenvironment (TME) may enhance MPN treatment. Monoclonal antibodies and vaccines targeting specific MPN epitopes show potential in augmenting tumor-related immune responses. Further research is needed to explore the application of next-generation ICIT in MPN treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Oncology
Naveen Pemmaraju, Prithviraj Bose, Raajit Rampal, Aaron T. Gerds, Angela Fleischman, Srdan Verstovsek
Summary: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, abnormal cytokine expression, cytopenias, and progressive bone marrow fibrosis. Ruxolitinib, an oral Janus kinase (JAK) 1 and JAK2 inhibitor, was the first approved agent for MF and has revolutionized the treatment approach. The understanding of MF has improved significantly due to targeted JAK1/JAK2 inhibition and extensive literature on ruxolitinib, leading to better management strategies and discussion on future treatment options.
LEUKEMIA & LYMPHOMA
(2023)
Review
Hematology
Chandan Saha, Claire Harrison
Summary: This article discusses the development and evidence base of Fedratinib, a new drug for the treatment of myelofibrosis. It addresses its efficacy, safety concerns, and future directions in targeted therapy for myelofibrosis. Fedratinib presents a much-needed treatment option, especially for patients who have failed Ruxolitinib.
EXPERT REVIEW OF HEMATOLOGY
(2022)
Article
Oncology
Juan-Carlos Hernandez-Boluda, David Martinez-Cuadron, Arturo Pereira, Rebeca Rodriguez-Veiga, Blanca Boluda, Cristina Gil, Sandra Casal-Marini, Josefina Serrano, Joaquin Martinez-Lopez, Juan Bergua, Lorenzo Algarra, Teresa Bernal, Jose-Luis Lopez-Lorenzo, Mercedes Colorado, Aurelio Lopez, Mar Tormo, Maria-Jose Sayas, Fernanda Trigo, Maria Lopez-Pavia, Jose-Antonio Perez-Simon, Esperanza Lavilla-Rubira, Carlos Rodriguez-Medina, Juan-Ignacio Rodriguez-Gutierrez, Miguel-Angel Sanz-Caballer, Pau Montesinos
Summary: This study evaluated the disease characteristics, treatment patterns, and outcomes in patients with AML developing from MPN or MDS/MPN. The results showed that intensive chemotherapy and hypomethylating agents had better survival outcomes compared to non-intensive chemotherapy, but responses were short-lived without allogeneic hematopoietic cell transplantation. The prior disease subtypes did not affect treatment response or survival.
Article
Hematology
Ping Cai, Suhui Liu, Lijuan Duan, Li Huo, Depei Wu, Suning Chen, Ruyu Yang, Xiaofei Yang
Summary: The translocation t(8;9) generates the fusion gene PCM1-JAK2, leading to continuous activation of JAK2 tyrosine kinase. t(8;9)/PCM1-JAK2 is the most common myelodysplastic/myeloproliferative neoplasm. Patients with this abnormality have similar features and JAK2 kinase inhibitor (ruxolitinib) is an effective treatment. However, the long-term remission results of ruxolitinib are varied, so it is important to determine the response to ruxolitinib. This study describes a patient with eosinophilia-associated myeloproliferative neoplasm with t(8;9)(p21;p24), who has achieved sustained response for >1 year since the administration of ruxolitinib.
ACTA HAEMATOLOGICA
(2023)
Article
Chemistry, Medicinal
Rhiannon Morris, Liesl Butler, Andrew Perkins, Nadia J. Kershaw, Jeffrey J. Babon
Summary: LNK is an adaptor protein that regulates cytokine signaling and constrains the activation of the JAK-STAT pathway. Mutations in LNK can lead to increased signaling and contribute to various hematological and inflammatory diseases.