Drug Information

Drug (ID: DG00620) and It's Reported Resistant Information

• Name: Ruxolitinib
• Synonyms: Ruxolitinib; 941678-49-5; INCB018424; Ruxolitinib (INCB018424); (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile; INCB-018424; UNII-82S8X8XX8H; (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; INCB 018424; 82S8X8XX8H; INC424; CHEBI:66919; (R)-ruxolitinib; C17H18N6; (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile; (betaR)-beta-Cyclopentyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1-propanenitrile; INCB18424; R-Ruxolitinib; INC-424; INCB-18424; Ruxolitinib [USAN:INN]; INCB 18424; (3R)-3-cyclopentyl-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)propanenitrile; INC 424; RXT; Ruxolitinib (USAN/INN); INCB18424,Ruxolitinib; SCHEMBL171319; GTPL5688; INCB018424 - Ruxolitinib; CHEMBL1789941; SCHEMBL16546708; HSDB 8259; DTXSID10240930; SYN1120; ACT06813; AMY24152; AOB87783; EX-A1670; BDBM50355501; MFCD12031592; NSC763371; NSC800874; s1378; ZINC43207851; AKOS016842401; BCP9000784; CCG-264889; CS-0864; DB08877; NSC-763371; NSC-800874; NCGC00244253-01; NCGC00244253-02; NCGC00244253-11; NCGC00244253-12; AC-24280; AS-18619; HY-50856; QC-11806; W9658; 1092939-15-5; A14955; A23578; D09959; AB01565782_02; Q7383611; BRD-K53972329-001-02-1; BRD-K53972329-001-03-9; (3R)-3-cyclopentyl-3-[4-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile; (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl)-3-cyclopentylpropanenitrile; 3-Cyclopentyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(beta-R)-1H-pyrazole-1-propanenitrile; A-Cyclopentyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(AR)-1H-pyrazole-1-propanenitrile; (3R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile;Ruxolitinib; 1H-Pyrazole-1-propanenitrile, beta-cyclopentyl-4-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)-,(betaR)-
• Indication:
  In total 6 Indication(s)
  Atopic dermatitis [ICD-11: EA80]; Approved; [1]
  Essential thrombocythemia [ICD-11: 3B63]; Approved; [1]
  Essential thrombocythemia [ICD-11: 3B63]; Approved; [1]
  High-risk myelofibrosis [ICD-11: 2A20]; Approved; [1]
  Pancreatic cancer [ICD-11: 2C10]; Approved; [1]
  Vitiligo [ICD-11: ED63]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Acute lymphocytic leukemia [ICD-11: 2B33]; [2]
  Chronic myeloid leukemia [ICD-11: 2A20]; [1]
  Myeloproliferative neoplasm [ICD-11: 2A22]; [3]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Hematologic cancer [ICD-11: MG24]; [4]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [5]
• Target: Janus kinase 1 (JAK-1); JAK1_HUMAN; [1]
• Target: Janus kinase 2 (JAK-2); JAK2_HUMAN; [1]
• Target: Urokinase plasminogen activator surface receptor (PLAUR); UPAR_HUMAN; [1]
• Formula: C17H18N6
• IsoSMILES: C1CCC(C1)[C@@H](CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3
• InChI: 1S/C17H18N6/c18-7-5-15(12-3-1-2-4-12)23-10-13(9-22-23)16-14-6-8-19-17(14)21-11-20-16/h6,8-12,15H,1-5H2,(H,19,20,21)/t15-/m1/s1
• InChIKey: HFNKQEVNSGCOJV-OAHLLOKOSA-N
• PubChem CID: 25126798
• ChEBI ID: CHEBI:66919
• TTD Drug ID: D04LKS
• DrugBank ID: DB08877

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [5]

• Molecule Alteration: Missense mutation; p.L857P (c.2570T>C)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: U4C cells; Acetabulum; Homo sapiens (Human); CVCL_D314
• In Vivo Model: Balb/c bone marrow transplantation mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Proliferation assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [5]

• Molecule Alteration: Missense mutation; p.V674A (c.2021T>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: U4C cells; Acetabulum; Homo sapiens (Human); CVCL_D314
• In Vivo Model: Balb/c bone marrow transplantation mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Proliferation assay

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [6]

• Molecule Alteration: Missense mutation; p.N610H (c.1828A>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: C57/BL6 mouse model; Mus musculus
• Experiment for Molecule Alteration: Sanger genomic DNA sequencing assay
• Experiment for Drug Resistance: MTS assay

Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [7]

• Molecule Alteration: Missense mutation; p.T640N (c.1919C>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T17 cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vivo Model: Balb/c bone marrow transplantation mouse model; Mus musculus
• Experiment for Molecule Alteration: Sanger sequencing assay; Western blotting analysis
• Experiment for Drug Resistance: Cytokine-independent growth assay

Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [6]

• Molecule Alteration: Missense mutation; p.N610S (c.1829A>G)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: C57/BL6 mouse model; Mus musculus
• Experiment for Molecule Alteration: Sanger genomic DNA sequencing assay
• Experiment for Drug Resistance: MTS assay

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.V617F
• Resistant Disease: Polycythaemia vera [ICD-11: 2A20.4]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: JAK2 mutation confers resistance to Ruxolitinib.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [8]

• Molecule Alteration: Function; Inhibition
• Sensitive Disease: Primary myelofibrosis [ICD-11: 2A20.2]
• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [9]

• Molecule Alteration: Missense mutation; p.T618I (c.1853C>T)
• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: BALB/C nude mouse xenograft model; Mus musculus

Atypical chronic myeloid leukemia [ICD-11: 2A41]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [10]

• Molecule Alteration: Missense mutation; p.T615A (c.1843A>G)
• Sensitive Disease: Atypical chronic myeloid leukemia [ICD-11: 2A41.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: The missense mutation p.T615A (c.1843A>G) in gene CSF3R cause the sensitivity of Ruxolitinib by unusual activation of pro-survival pathway

Key Molecule: Granulocyte colony-stimulating factor receptor (CSF3R) [10]

• Molecule Alteration: Missense mutation; p.T618I (c.1853C>T)
• Sensitive Disease: Atypical chronic myeloid leukemia [ICD-11: 2A41.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: The missense mutation p.T618I (c.1853C>T) in gene CSF3R cause the sensitivity of Ruxolitinib by unusual activation of pro-survival pathway

Acute myeloid leukemia [ICD-11: 2A60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [11]

• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of Ruxolitinib by aberration of the drug's therapeutic target

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.R938Q (c.2813G>A)
• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Mutations within the kinase domain of JAK2 are associated with resistance to type I JAK inhibitors.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Janus kinase 1 (JAK-1) [12]

• Molecule Alteration: Missense mutation; p.S646F (c.1937C>T)
• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Phosphoflow analysis
• Mechanism Description: The missense mutation p.S646F (c.1937C>T) in gene JAK1 cause the sensitivity of Ruxolitinib by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [12]

• Molecule Alteration: Missense mutation; p.R683G (c.2047A>G)
• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interleukin-7 receptor subunit alpha (IL7R) [12]

• Molecule Alteration: Missense mutation; p.S185C (c.553A>T)
• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [13]

• Molecule Alteration: Missense mutation; p.F694L (c.2080T>C)
• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Inhibition; hsa04030

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) [4]

• Molecule Alteration: Missense mutation; p.R867Q (c.2600G>A)
• Resistant Disease: Hematologic Cancer [ICD-11: MG24.Y]
• 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 blotting analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Calreticulin (CALR) [14]

• Molecule Alteration: FS-insertion; p.K385fs*47 (c.1153_1154insTAATT)
• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• 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 blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Liver cancer [ICD-11: 2C12]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Janus kinase 1 (JAK-1) [15]

• Molecule Alteration: Missense mutation; p.S703I (c.2108G>T)
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: JAK1 cells; N.A.; .; N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Tumor volume measurement assay

ICD-03: Blood/blood-forming organs diseases

Hereditary elliptocytosis [ICD-11: 3A10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Von Hippel-Lindau disease tumor suppressor (VHL) [16]

• Molecule Alteration: Missense mutation; p.R200W (c.598C>T)
• Sensitive Disease: Familial erythrocytosis 2 [ICD-11: 3A10.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Inhibition; hsa04030

References

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• Ref 2: A novel somatic JAK2 kinase-domain mutation in pediatric acute lymphoblastic leukemia with rapid on-treatment development of LOHCancer Genet. 2017 Oct;216-217:86-90. doi: 10.1016/j.cancergen.2017.07.008. Epub 2017 Jul 31.
• Ref 3: Management of challenging myelofibrosis after JAK inhibitor failure and/or progressionBlood Rev. 2020 Jul;42:100716. doi: 10.1016/j.blre.2020.100716. Epub 2020 May 30.
• Ref 4: 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 5: Distinct Acute Lymphoblastic Leukemia (ALL)-associated Janus Kinase 3 (JAK3) Mutants Exhibit Different Cytokine-Receptor Requirements and JAK Inhibitor SpecificitiesJ Biol Chem. 2015 Nov 27;290(48):29022-34. doi: 10.1074/jbc.M115.670224. Epub 2015 Oct 7.
• Ref 6: A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in LeukemiaCancer Res. 2018 Dec 15;78(24):6762-6770. doi: 10.1158/0008-5472.CAN-18-1638. Epub 2018 Oct 22.
• Ref 7: The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618IClin Cancer Res. 2016 Feb 1;22(3):757-64. doi: 10.1158/1078-0432.CCR-14-3100. Epub 2015 Oct 16.
• Ref 8: 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 9: The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibitionBlood. 2013 Nov 21;122(22):3628-31. doi: 10.1182/blood-2013-06-509976. Epub 2013 Sep 30.
• Ref 10: Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CMLN Engl J Med. 2013 May 9;368(19):1781-90. doi: 10.1056/NEJMoa1214514.
• Ref 11: Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemiaBlood. 2012 May 17;119(20):4614-8. doi: 10.1182/blood-2011-12-400051. Epub 2012 Mar 15.
• Ref 12: Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemiaBlood. 2012 Oct 25;120(17):3510-8. doi: 10.1182/blood-2012-03-415448. Epub 2012 Sep 6.
• Ref 13: Integration of ruxolitinib into dose-intensified therapy targeted against a novel JAK2 F694L mutation in B-precursor acute lymphoblastic leukemiaPediatr Blood Cancer. 2017 May;64(5):10.1002/pbc.26328. doi: 10.1002/pbc.26328. Epub 2016 Nov 15.
• Ref 14: Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutantsBlood. 2016 Mar 10;127(10):1325-35. doi: 10.1182/blood-2015-11-681932. Epub 2015 Dec 14.
• Ref 15: Activating JAK1 mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinomaOncotarget. 2016 Feb 2;7(5):5461-9. doi: 10.18632/oncotarget.6684.
• Ref 16: Clinical Improvement with JAK2 Inhibition in Chuvash PolycythemiaN Engl J Med. 2016 Aug 4;375(5):494-6. doi: 10.1056/NEJMc1600337.