Drug Information

Drug (ID: DG00230) and It's Reported Resistant Information

• Name: Bosutinib
• Synonyms: SKI 606; SKI606; Bosutinib (USAN); PF-5208763; SKI-606; Xy]-3-quinolinecarbonitrile; 4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)-3-quinolinecarbonitrile; 4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile; 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propo; 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile; Bosutinib (BCR-ABL inhibitor 3rd gen)
• Indication:
  In total 1 Indication(s)
  Breast cancer [ICD-11: 2C60]; Approved; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Chronic myeloid leukemia [ICD-11: 2A20]; [3]
• Target: Proto-oncogene c-Src (SRC); SRC_HUMAN; [1]
• Target: Tyrosine-protein kinase ABL1 (ABL); ABL1_HUMAN; [2]
• Formula: C26H29Cl2N5O3
• IsoSMILES: CN1CCN(CC1)CCCOC2=C(C=C3C(=C2)N=CC(=C3NC4=CC(=C(C=C4Cl)Cl)OC)C#N)OC
• InChI: 1S/C26H29Cl2N5O3/c1-32-6-8-33(9-7-32)5-4-10-36-25-13-21-18(11-24(25)35-3)26(17(15-29)16-30-21)31-22-14-23(34-2)20(28)12-19(22)27/h11-14,16H,4-10H2,1-3H3,(H,30,31)
• InChIKey: UBPYILGKFZZVDX-UHFFFAOYSA-N
• PubChem CID: 5328940
• ChEBI ID: CHEBI:39112
• TTD Drug ID: D0OB0F
• VARIDT ID: DR00253
• INTEDE ID: DR0224
• DrugBank ID: DB06616

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

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 ABL1 (ABL1) [3]

• Molecule Alteration: Missense mutation; p.F359V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Patients with more than one BCR-ABL1 mutation fare worse than those with no or one mutation.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [3]

• Molecule Alteration: Missense mutation; p.M351T
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Overall survival assay; Event-free survival (EFS) assay
• Mechanism Description: Patients with more than one BCR-ABL1 mutation fare worse than those with no or one mutation.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [4]

• Molecule Alteration: Missense mutation; p.F359I
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Tritiated thymidine incorporation assay
• Mechanism Description: L248R was identified in a patient with lymphoid Blast Crisis (BC) CML (Patient no. 1), in cis with a pre-existing mutation. The patient initially presented with an imatinib-resistant F359I mutation.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [4]

• Molecule Alteration: Missense mutation; p.L248R
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Tritiated thymidine incorporation assay
• Mechanism Description: Mutations may impair TkI activity by directly or indirectly impairing the drug binding to the protein. We report the discovery of three new BCR/ABL mutations, L248R, T315V, and F317R identified in two patients with CML (L248R and T315V) and in one patient with Ph+ acute lymphoblastic leukemia (ALL) (F317R).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [1], [2]

• Molecule Alteration: Missense mutation; p.G12V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT signaling pathway; Activation; hsa04030
• Cell Pathway Regulation: RAF/KRAS/MEK signaling pathway; Activation; hsa04010
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay; Sanger Sequencing assay
• Mechanism Description: This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.

References

• Ref 1: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013 Aug 8;122(6):872-84. doi: 10.1182/blood-2013-05-501569. Epub 2013 Jun 26.
• Ref 2: Dissecting Genomic Aberrations in Myeloproliferative Neoplasms by Multiplex-PCR and Next Generation Sequencing. PLoS One. 2015 Apr 20;10(4):e0123476. doi: 10.1371/journal.pone.0123476. eCollection 2015.
• Ref 3: Outcome of patients with chronic myeloid leukemia with multiple ABL1 kinase domain mutations receiving tyrosine kinase inhibitor therapy. Haematologica. 2011 Jun;96(6):918-21. doi: 10.3324/haematol.2010.039321. Epub 2011 Feb 28.
• Ref 4: Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors. Am J Hematol. 2012 Nov;87(11):E125-8. doi: 10.1002/ajh.23338. Epub 2012 Oct 9.