Drug Information

Drug (ID: DG01239) and It's Reported Resistant Information

• Name: Fedratinib
• Synonyms: Fedratinib; 936091-26-8; Tg-101348; TG101348; SAR302503; N-(tert-butyl)-3-((5-methyl-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide; TG 101348; SAR-302503; Fedratinib (SAR302503, TG101348); SAR 302503; UNII-6L1XP550I6; TG101348 (SAR302503); N-(1,1-Dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]benzenesulfonamide; CHEMBL1287853; C27H36N6O3S; 6L1XP550I6; 936091-26-8 (free base); N-tert-butyl-3-(5-methyl-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide; N-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzenesulfonamide; Inrebic; Fedratinib [USAN:INN]; 2TA; Fedratinib (USAN/INN); Fedratinib TG101348; TG101348(Fedratinib); Fedratinib (TG101348); MLS006011155; SCHEMBL263741; GTPL5716; CHEBI:91408; AOB2041; DTXSID90239483; EX-A170; SYN1104; HMS3295I03; HMS3656L19; HMS3744G17; HMS3868L03; BCP02300; BDBM50332294; MFCD12922515; NSC767600; NSC800099; s2736; ZINC19862646; AKOS015842621; CCG-264990; CS-0052; DB12500; EX-5961; NSC-767600; NSC-800099; SB14604; NCGC00244252-01; NCGC00244252-07; AC-30260; AS-16248; Benzenesulfonamide, N-(1,1-dimethylethyl)-3-((5-methyl-2-((4-(2-(1-pyrrolidinyl)ethoxy)phenyl)amino)-4-pyrimidinyl)amino)-; DA-40258; HY-10409; N-Tert-butyl-3-(5-methyl-2-(4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino)-pyrimidin-4-ylamino)-benzenesulfonamide; N-tert-butyl-3-[[5-methyl-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]pyrimidin-4-yl]amino]benzenesulfonamide; SMR004702929; DB-079623; FT-0705969; FT-0763396; FT-0766818; SW218187-2; Y0268; A25534; D10630; F17372; SAR302503 (TG-101348); 091D268; J-523769; Q7670147; BRD-K12502280-001-01-5; 945381-69-1; Fedratinib; ; ; N-(1,1-Dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]-benzenesulfonamide; N-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzene-1-sulfonamide
• Indication:
  In total 1 Indication(s)
  Myelofibrosis [ICD-11: 2A20]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Myeloproliferative neoplasm [ICD-11: 2A22]; [2]
  Hematologic cancer [ICD-11: MG24]; [3]
• Target: Janus kinase 2 (JAK-2); JAK2_HUMAN; [1]
• Formula: C27H36N6O3S
• IsoSMILES: CC1=CN=C(N=C1NC2=CC(=CC=C2)S(=O)(=O)NC(C)(C)C)NC3=CC=C(C=C3)OCCN4CCCC4
• 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)
• InChIKey: JOOXLOJCABQBSG-UHFFFAOYSA-N
• PubChem CID: 16722836
• ChEBI ID: CHEBI:91408
• TTD Drug ID: D0G8BM
• DrugBank ID: DB12500

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [1]

• Sensitive Disease: Primary myelofibrosis [ICD-11: 2A20.2]
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: In non-transplant candidates, conventional treatment for anemia includes androgens, prednisone, thalidomide, and danazol; for symptomatic splenomegaly, hydroxyurea and ruxolitinib; and for constitutional symptoms, ruxolitinib. Fedratinib, another JAK2 inhibitor, has now been FDA-approved for use in ruxolitinib failures.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [4]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of Fedratinib by aberration of the drug's therapeutic target

Myeloproliferative neoplasm [ICD-11: 2A22]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Mutation; V617F+L902Q+E1028K
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Mutation; V617F+L902Q+R938E
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Mutation; V617F+L902Q+R947Q
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites.

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Mutation; V617F+Y931C
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Mutation; V617F+L902Q+E1028K
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: MTS-based assay
• Mechanism Description: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites.

Hematologic cancer [ICD-11: 2B3Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [3]

• Resistant Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Molecule Alteration: Missense mutation; p.R867Q (c.2600G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

References

• Ref 1: Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management .Am J Hematol. 2021 Jan;96(1):145-162. doi: 10.1002/ajh.26050. Epub 2020 Dec 2. 10.1002/ajh.26050
• Ref 2: Type II mode of JAK2 inhibition and destabilization are potential therapeutic approaches against the ruxolitinib resistance driven myeloproliferative neoplasms. Front Oncol. 2024 Jul 18;14:1430833.
• Ref 3: Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitorsBlood. 2014 Feb 27;123(9):1372-83. doi: 10.1182/blood-2013-05-504555. Epub 2014 Jan 7.
• Ref 4: Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia veraCancer Cell. 2008 Apr;13(4):311-20. doi: 10.1016/j.ccr.2008.02.009.