THERAPEUTIC AGENT FOR CHRONIC MYELOID LEUKEMIA
|Posted date||Feb 16, 2017|
|International application number||2016JP060803|
|International publication number||WO 2016159301|
|Date of international filing||Mar 31, 2016|
|Date of international publication||Oct 6, 2016|
|Title||THERAPEUTIC AGENT FOR CHRONIC MYELOID LEUKEMIA|
|Abstract||A safe and effective CML stem cell remover, a TKI-resistant suppressant, and a multi-kinase inhibitor-resistant suppressant are provided as a result of revealing this novel signal transduction pathway involved in maintaining chronic myeloid leukemia stem cells and selectively inhibiting the signal. With this, a therapeutic drug for relapse of CML and Ph+ALL and a preventative drug for relapse of CML and Ph+ALL are provided. The therapeutic agent for chronic myeloid leukemia contains a selective inhibitor of the p38 MAPK signal. The therapeutic agent is combined with a tyrosine kinase inhibitor or a multi kinase inhibitor.|
|Outline of related art and contending technology||
Chronic myelogenous leukemia (CML) is, the origin of the hematopoietic stem cells and bone marrow proliferative disease onset, after the chronic phase of several years, transition through acute exhibit serious form travels to the conversion phase. In the treatment of CML, chronic phase to acute therapy thorough conversion into S-migration becomes important. In patients with Philadelphia chromosome called CML chromosomal translocation t (q34;q22) (9;22) observed, by this translocation, the constitutively activated BCR-ABL tyrosine kinase can be expressed with a fusion protein, known as the cause of the development of CML. BCR-ABL tyrosine kinase can be a self-phosphorylate cellular substrates, cell growth, transformation, apoptosis-suppressing relating to various cells by activating intracellular signaling, involved in the development of CML.
For the treatment of CML for tyrosine kinase inhibitors (TKI) imatinib ABL (on city agent is the mesylate salt) have been developed, which significantly improves the treatment result of the patient CML. Imatinib, tyrosine kinases bind competitively to the ATP binding site, followed by substrate phosphorylation by inhibiting signal transduction, cell proliferation, induction of apoptosis CML cells selectively to injury. This imatinib or, further highly therapeutically effective, second-generation TKI of nilotinib, dasatinib, bosutinib, (IY5511) in the treatment of patients CML radochinibu is used. However, after treatment in a patient such as CML TKI imatinib, is not lost TKI CML (CML treatment-refractory relapse) is to be a significant clinical problem. In recent years, as a mechanism of this recurrence, T315I (imatinib binding site 315 the threonine residue at position is substituted with a serine) represented by a point mutation of BCR-ABL TKI resistance appears clear. Expressing TKI CML BCR-ABL1 resistance of the patient as a therapeutic agent, has been developed ponachinibu multikinase inhibitor, in the United States and EU, pretreatment TKI CML resistance or intolerable to the subject which has been approved. However, resistance TKI CML CML cell growth source stem cells cannot be completely excluded, is taken out of the treatment ponachinibu recurrence is a possibility. Therefore, the patient must continue treatment continued ponachinibu not. In addition, generate TKI resistance CML stem cells as a source, a plurality of gene mutations (compound mutation) having CML stem cells occurs, may cause further ponachinibu resistance becomes. Therefore, in order to cure CML, to eradicate CML stem cells is a need for the development of treatment methods.
A number of drug-suppressed CML stem cells has been reported that, in combination with the treatment TKI CML have been proposed. For example, the present inventors previously, TGF-β-FOXO(Patent Document 1) and signal TGF-β-Smad signal by inhibiting (Patent Document 2), CML stem cells can be efficiently removed, could inhibit TKI resistance, by a combination of further TKI, CML CML stem cells and differentiated cells found at the same time can be eliminated, and the recurrence after remission TKI resistance acquisition of novel reduction of the risk of developed a means of treating CML.
However, signaling pathways p38 MAPK(mitogen-activated protein kinase), environmental stress or an ultraviolet, apoptosis, involved in the inflammatory response is known. In addition, in recent years, various cancers reported activation of p38 (non-patent document 1), a selective inhibitor of LY2228820 p38 a plurality of cancer model (melanoma, non-small cell lung cancer, ovarian cancer, glioma, myeloma, breast cancer) in delayed tumor growth and (non-patent document 2) a report. However, the effect of p38 in cancer, tumor and its microenvironment and intimately involved with the interaction of the, thought to have largely different depending on the type of cancer. In the context of particularly CML, activation of p38 induced apoptosis in the cell CML (non-patent document 3, 4), to inhibit CML cell lines and apoptosis in K562 cells is suppressed p38 (non-patent document 5, 6) are reported. In addition, dasatinib is leukemia to the therapeutic effect of the activation of the p38 essential (non-patent document 7) a report.
|Scope of claims||
|IPC(International Patent Classification)||
National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
Contact Information for " THERAPEUTIC AGENT FOR CHRONIC MYELOID LEUKEMIA "
- HIROSHIMA UNIVERSITY Collaborative Research Center Intellectual Property Division
- URL: https://www.hiroshima-u.ac.jp/iagcc
- Address: 1-3-2 Kagamiyama Higashi-Hiroshima, Hiroshima, Japan , 739-8511
- Fax: 81-82-424-6133