fedratinib   Click here for help

GtoPdb Ligand ID: 5716

Synonyms: Inrebic® | SAR302503 | TG-101348 | TG101348
Approved drug PDB Ligand
fedratinib is an approved drug (FDA (2019), EMA (2021))
Compound class: Synthetic organic
Comment: Fedratinib (TG‑101348) was initially reported as an orally active JAK2-FLT3 kinase inhibitor, with biological activity via JAK2 inhibition [6]. More recently, this compound has been discovered to function, in addition, as a BRD4 (bromodomain) inhibitor [2,4]. It is suggested that TG‑101348 be termed a dual kinase-bromodomain inhibitor. Fedratinib is been identified and officially approved as an alternative to the JAK1/2 inhibitor ruxolitinib for the treatment of primary and secondary myelofibrosis [1].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 3
Rotatable bonds 11
Topological polar surface area 116.86
Molecular weight 524.26
XLogP 4.26
No. Lipinski's rules broken 1
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Canonical SMILES Cc1cnc(nc1Nc1cccc(c1)S(=O)(=O)NC(C)(C)C)Nc1ccc(cc1)OCCN1CCCC1
Isomeric SMILES Cc1cnc(nc1Nc1cccc(c1)S(=O)(=O)NC(C)(C)C)Nc1ccc(cc1)OCCN1CCCC1
InChI InChI=1S/C27H36N6O3S/c1-20-19-28-26(30-21-10-12-23(13-11-21)36-17-16-33-14-5-6-15-33)31-25(20)29-22-8-7-9-24(18-22)37(34,35)32-27(2,3)4/h7-13,18-19,32H,5-6,14-17H2,1-4H3,(H2,28,29,30,31)
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Summary of Clinical Use Click here for help
Phase 3 clinical trial NCT01437787 has been completed. Thijs study evaluated the efficacy of fedratinib (as research code SAR302503) as a treatment for myelofibrosis. In August 2019 the FDA approved fedratinib (trade named Inrebic®) as a treatment for intermediate-2 or high-risk primary or secondary myelofibrosis. Inrebic® has a Boxed Warning for serious and fatal encephalopathy, including Wernicke's encephalopathy.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Abnormal activation of JAK2 is associated with myeloproliferative neoplasms, including myelofibrosis and polycythemia vera. By inhibiting elevated levels of JAK2 activity, fedratinib reduces downstream activation (phosphorylation) of STAT3 and STAT5 proteins and ultimately reduces cell proliferation, and induces apoptotic cell death, to mediate an improvement in disease-associated symptoms.