Fedratinib

Fedratinib
Clinical data
Trade names	Inrebic
Other names	SAR302503; TG101348
AHFS/Drugs.com	Monograph
License data	US DailyMed: Inrebic;
Pregnancy; category	US: N (Not classified yet) ;
Routes of; administration	Oral
Drug class	Antineoplastic agent
ATC code	L01XE57 (WHO) ;
Legal status
Legal status	US: ℞-only ;
Identifiers
	IUPAC name N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide;
CAS Number	936091-26-8 ;
PubChem CID	16722836;
DrugBank	DB12500;
ChemSpider	17626393;
UNII	6L1XP550I6;
KEGG	D10630;
ChEBI	CHEBI:91408;
ChEMBL	ChEMBL1287853;
CompTox Dashboard (EPA)	DTXSID90239483 ;
Chemical and physical data
Formula	C27H36N6O3S
Molar mass	524.68 g·mol−1
3D model (JSmol)	Interactive image;
Density	1.247 ± 0.06 g/cm3 g/cm3
	SMILES CC1=CN=C(N=C1NC2=CC(=CC=C2)S(=O)(=O)NC(C)(C)C)NC3=CC=C(C=C3)OCCN4CCCC4;
	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); Key:JOOXLOJCABQBSG-UHFFFAOYSA-N;
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Fedratinib (trade name Inrebic), used in the form of fedratinib hydrochloride, is an orally available semi-selective inhibitor of Janus kinase 2 (JAK-2) developed for the treatment of patients with myeloproliferative diseases including myelofibrosis.[1][2] Fedratinib acts as a competitive inhibitor of protein kinase JAK-2 with IC₅₀=6 nM; related kinases FLT3 and RET are also sensitive, with IC₅₀=25 nM and IC₅₀=17 nM, respectively. Significantly less activity was observed against other tyrosine kinases including JAK3 (IC₅₀=169 nM).[3] In treated cells the inhibitor blocks downstream cellular signalling (JAK-STAT) leading to suppression of proliferation and induction of apoptosis. It was approved by FDA on 16 August 2019.[1]

Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients with myelofibrosis frequently harbor JAK-STAT activating mutations that are sensitive to TG101348. Phase I trial results focused on safety and efficacy of Fedratinib in patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis have been published in 2011.[4]

History

Fedratinib was originally discovered at TargeGen. In 2010, Sanofi-Aventis acquired TargeGen and continued development of fedratinib until 2013. In 2016, Impact Biomedicines acquired the rights to fedratinib from Sanofi and continued its development for the treatment of myelofibrosis and polycythemia vera. In January 2018, the drug's rights were transferred to Celgene with their purchase of Impact Biomedicines.[5]

Fedratinib was approved for use in the United States in August 2019.[1][2]

The U.S. Food and Drug Administration (FDA) granted the application for Fedratinib priority review designation and orphan drug designation.[1] The FDA granted the approval of Inrebic to Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation.[1]

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References

"FDA approves treatment for patients with rare bone marrow disorder". U.S. Food and Drug Administration (FDA) (Press release). 16 August 2019. Archived from the original on 21 November 2019. Retrieved 16 August 2019. This article incorporates text from this source, which is in the public domain.
"Drug Trials Snapshots: Inrebic". U.S. Food and Drug Administration (FDA). 30 August 2019. Archived from the original on 21 November 2019. Retrieved 20 November 2019. This article incorporates text from this source, which is in the public domain.
Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G, Finke C, Mak CC, Mesa R, Zhu H, Soll R, Gilliland DG, Tefferi A (August 2007). "TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations". Leukemia. 21 (8): 1658–1668. PMID 17541402.
Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, Silverman MH, Gilliland DG, Shorr J, Tefferi A (March 2011). "Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis". Journal of Clinical Oncology. 29 (7): 789–796. doi:10.1200/JCO.2010.32.8021. PMC 4979099. PMID 21220608.
"Celgene to Acquire Impact Biomedicines, Adding Fedratinib to Its Pipeline of Novel Therapies for Hematologic Malignancies". Celgene (Press release). 7 January 2018. Retrieved 18 January 2018.

External links

"Fedratinib". Drug Information Portal. U.S. National Library of Medicine.

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[FDA_PR-1] "FDA approves treatment for patients with rare bone marrow disorder". U.S. Food and Drug Administration (FDA) (Press release). 16 August 2019. Archived from the original on 21 November 2019. Retrieved 16 August 2019. This article incorporates text from this source, which is in the public domain.

[FDA_Snapshot-2] "Drug Trials Snapshots: Inrebic". U.S. Food and Drug Administration (FDA). 30 August 2019. Archived from the original on 21 November 2019. Retrieved 20 November 2019. This article incorporates text from this source, which is in the public domain.

[3] Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G, Finke C, Mak CC, Mesa R, Zhu H, Soll R, Gilliland DG, Tefferi A (August 2007). "TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations". Leukemia. 21 (8): 1658–1668. PMID 17541402.

[4] Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, Silverman MH, Gilliland DG, Shorr J, Tefferi A (March 2011). "Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis". Journal of Clinical Oncology. 29 (7): 789–796. doi:10.1200/JCO.2010.32.8021. PMC 4979099. PMID 21220608.

[5] "Celgene to Acquire Impact Biomedicines, Adding Fedratinib to Its Pipeline of Novel Therapies for Hematologic Malignancies". Celgene (Press release). 7 January 2018. Retrieved 18 January 2018.