期刊
BLOOD
卷 130, 期 9, 页码 1114-1124出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-09-741983
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资金
- Bayer AG Pharmaceuticals Division
- National Cancer Center Research and Development Fund [26-A-4]
- Japan Agency for Medical Research and Development [16cm0106301h0001, 15ck0106159h0001, 15ck0106132h0002]
- [16H04713]
- Grants-in-Aid for Scientific Research [16K19584, 16H04713] Funding Source: KAKEN
Cyclin-dependent kinase 9 (CDK9), a subunit of the positive transcription elongation factor b (P-TEFb) complex, regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). The deregulation of CDK9/PTEFb has important implications for many cancer types. BAY 1143572 is a novel and highly selective CDK9/P-TEFb inhibitor currently being investigated in phase 1 studies. Weevaluated the therapeutic potential ofBAY1143572 in adult T-cell leukemia/lymphoma (ATL). As a result of CDK9 inhibition and subsequent inhibition of phosphorylation at serine 2 of the RNAPII CTD, BAY1143572 decreased c-Mycand Mcl-1 levels in ATL-derived or human T-cell lymphotropic virus type-1 (HTLV-1)-transformed lines and primary ATL cells tested, leading to their growth inhibition and apoptosis. Median inhibitory concentrations for BAY 1143572 in ATL-derived or HTLV-1-transformed lines (n = 8), primary ATL cells (n=11), and CD4 1 cells fromhealthy volunteers (n=5) were 0.535, 0.30, and 0.36 mM, respectively. Next, NOG mice were used as recipients of tumor cells from an ATL patient. BAY 1143572-treated ATL-bearing mice (once daily 12.5 mg/kg oral application) demonstrated significantly decreased ATL cell infiltration of the liver and bone marrow, as well as decreased human soluble interleukin-2 receptor levels in serum (reflecting the ATL tumor burden), compared with untreated mice (n = 8 for both). BAY 1143572-treated ATL-bearingmice demonstrated significantly prolonged survival compared with untreated ATL-bearing mice (n=7 for both). Collectively, this study indicates thatBAY1143572showedstrongpotential as anovel treatmentof ATL.
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