Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C30H31F3N8O |
Molecular Weight | 576.6153 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CN(C)[C@H]1CCN(CC2=C(C=C(C=C2)C(=O)NC3=CC=C(C)C(NC4=NC=CC(=N4)C5=CN=CN=C5)=C3)C(F)(F)F)C1
InChI
InChIKey=ZGBAJMQHJDFTQJ-DEOSSOPVSA-N
InChI=1S/C30H31F3N8O/c1-19-4-7-23(13-27(19)39-29-36-10-8-26(38-29)22-14-34-18-35-15-22)37-28(42)20-5-6-21(25(12-20)30(31,32)33)16-41-11-9-24(17-41)40(2)3/h4-8,10,12-15,18,24H,9,11,16-17H2,1-3H3,(H,37,42)(H,36,38,39)/t24-/m0/s1
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/21154127Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/20310049
http://www.med-chemist.com/2010/06/bafetinib-demonstrates-significant.html
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21154127
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/20310049
http://www.med-chemist.com/2010/06/bafetinib-demonstrates-significant.html
Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. Besides Abl, bafetinib targets the Src family kinase Lyn, which has been associated with resistance to imatinib in CML. In preclinical studies, bafetinib was 25- to 55-fold more potent than imatinib in vitro and ≥ 10-fold more potent in vivo. Bafetinibinhibits 12 of the 13 most frequent imatinib-resistant Bcr-Abl point mutations, but not a Thr315Ile mutation. A small fraction of bafetinib crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Data from a phase I clinical trial conducted in patients with imatinib-resistant or -intolerant CML have confirmed that bafetinib has clinical activity in this setting, inducing a major cytogenetic response in 19% of those patients in chronic phase. Currently, bafetinib is being developed in two phase II clinical trials for patients with B-cell chronic lymphocytic leukemia and prostate cancer, and a trial is in progress for patients with brain tumors. In 2005, the compound was licensed to Innovive Pharmaceuticals (acquired by CytRx Oncology in 2008) by Nippon Shinyaku on a worldwide basis, with the exception of Japan, for the treatment of CML. Orphan drug designation was assigned to the compound for the treatment of CML in the U.S in 2007 and in the E.U. in 2010. Bafetinib is in phase II for the treatment of hormone-refractory prostate cancer and chronic lymphocytic leukemia.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21154127 | https://www.ncbi.nlm.nih.gov/pubmed/23741470
Curator's Comment: Bafetinib crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Bafetinib is capable of preventing the progression of dopaminergic neuronal damage in a toxin-induced C57 mouse model of PD.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1862 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17376680 |
26.0 nM [IC50] | ||
Target ID: CHEMBL3905 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16105974 |
19.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
164 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23380277 |
360 mg 2 times / day multiple, oral dose: 360 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BAFETINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
129 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23380277 |
360 mg 2 times / day single, oral dose: 360 mg route of administration: Oral experiment type: SINGLE co-administered: |
BAFETINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
661 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16105974 |
30 mg/kg single, oral dose: 30 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
BAFETINIB plasma | Mus musculus population: UNKNOWN age: ADULT sex: FEMALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1000 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23380277 |
360 mg 2 times / day multiple, oral dose: 360 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BAFETINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
522 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23380277 |
360 mg 2 times / day single, oral dose: 360 mg route of administration: Oral experiment type: SINGLE co-administered: |
BAFETINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
2294 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16105974 |
30 mg/kg single, oral dose: 30 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
BAFETINIB plasma | Mus musculus population: UNKNOWN age: ADULT sex: FEMALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16105974 |
30 mg/kg single, oral dose: 30 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
BAFETINIB plasma | Mus musculus population: UNKNOWN age: ADULT sex: FEMALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
480 mg 2 times / day multiple, oral Highest studied dose Dose: 480 mg, 2 times / day Route: oral Route: multiple Dose: 480 mg, 2 times / day Sources: |
unhealthy n = 5 Health Status: unhealthy Condition: chronic myeloid leukemia Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: |
DLT: transaminase elevation, thrombocytopenia... Dose limiting toxicities: transaminase elevation Sources: thrombocytopenia |
240 mg 2 times / day multiple, oral (unknown) RP2D Dose: 240 mg, 2 times / day Route: oral Route: multiple Dose: 240 mg, 2 times / day Sources: |
unhealthy n = 17 Health Status: unhealthy Condition: CML - chronic Myelogenous Leukemia Sex: M+F Food Status: UNKNOWN Population Size: 17 Sources: |
Other AEs: ALT elevation, AST elevation... Other AEs: ALT elevation (grade 3, 1 pt) Sources: AST elevation (grade 2, 1 pt) transaminase elevation |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
thrombocytopenia | DLT | 480 mg 2 times / day multiple, oral Highest studied dose Dose: 480 mg, 2 times / day Route: oral Route: multiple Dose: 480 mg, 2 times / day Sources: |
unhealthy n = 5 Health Status: unhealthy Condition: chronic myeloid leukemia Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: |
transaminase elevation | DLT | 480 mg 2 times / day multiple, oral Highest studied dose Dose: 480 mg, 2 times / day Route: oral Route: multiple Dose: 480 mg, 2 times / day Sources: |
unhealthy n = 5 Health Status: unhealthy Condition: chronic myeloid leukemia Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: |
transaminase elevation | 240 mg 2 times / day multiple, oral (unknown) RP2D Dose: 240 mg, 2 times / day Route: oral Route: multiple Dose: 240 mg, 2 times / day Sources: |
unhealthy n = 17 Health Status: unhealthy Condition: CML - chronic Myelogenous Leukemia Sex: M+F Food Status: UNKNOWN Population Size: 17 Sources: |
|
AST elevation | grade 2, 1 pt | 240 mg 2 times / day multiple, oral (unknown) RP2D Dose: 240 mg, 2 times / day Route: oral Route: multiple Dose: 240 mg, 2 times / day Sources: |
unhealthy n = 17 Health Status: unhealthy Condition: CML - chronic Myelogenous Leukemia Sex: M+F Food Status: UNKNOWN Population Size: 17 Sources: |
ALT elevation | grade 3, 1 pt | 240 mg 2 times / day multiple, oral (unknown) RP2D Dose: 240 mg, 2 times / day Route: oral Route: multiple Dose: 240 mg, 2 times / day Sources: |
unhealthy n = 17 Health Status: unhealthy Condition: CML - chronic Myelogenous Leukemia Sex: M+F Food Status: UNKNOWN Population Size: 17 Sources: |
PubMed
Title | Date | PubMed |
---|---|---|
INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. | 2007 Jan 1 |
|
Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters. | 2016 May 9 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT01144260
250 mg orally twice daily
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16105974
Bafetinib blocks WT Bcr-Abl autophosphorylation and its downstream kinase activity with IC50 of 11 nM and 22 nM in K562 and 293T cells, respectively.
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Classification Tree | Code System | Code | ||
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EU-Orphan Drug |
EU/3/10/731
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NCI_THESAURUS |
C1967
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FDA ORPHAN DRUG |
233206
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NCI_THESAURUS |
C129825
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Bafetinib
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100000141657
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CHEMBL206834
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NVW4Z03I9B
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SUB96036
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C62516
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ACTIVE MOIETY