Lead optimization of HMBA to develop potent HEXIM1 inducers.
نویسندگان
چکیده
The potency of a series of Hexamethylene bis-acetamide (HMBA) derivatives inducing Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) was determined in LNCaP prostate cancer cells. Several compounds with unsymmetrical structures showed significantly improved activity. Distinct from HMBA, these analogs have increased hydrophobicity and can improve the short half-life of HMBA, which is one of the factors that have limited the application of HMBA in clinics. The unsymmetrical scaffolds of the new analogs provide the basis for further lead optimization of the compounds using combinatorial chemistry strategy.
منابع مشابه
HMBA Releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K/Akt and Activates HIV Transcription
Hexamethylene bisacetamide (HMBA) is a potent inducer of cell differentiation and HIV production in chronically infected cells. However, its mechanism of action remains poorly defined. In this study, we demonstrate that HMBA activates transiently the PI3K/Akt pathway, which leads to the phosphorylation of HEXIM1 and the subsequent release of active positive transcription elongation factor b (P-...
متن کاملSecond generation hybrid polar compounds are potent inducers of transformed cell differentiation.
Hybrid polar compounds, of which hexamethylenebisacetamide (HMBA) is the prototype, are potent inducers of differentiation of murine erythroleukemia (MEL) cells and a wide variety of other transformed cells. HMBA has been shown to induce differentiation of neoplastic cells in patients, but is not an adequate therapeutic agent because of dose-limiting toxicity. We report on a group of three pote...
متن کاملA class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases.
Hybrid polar compounds (HPCs) have been synthesized that induce terminal differentiation and/or apoptosis in various transformed cells. We have previously reported on the development of the second-generation HPCs suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bishydroxamide (CBHA) that are 2,000-fold more potent inducers on a molar basis than the prototype HPC hexamethylene b...
متن کاملCombination cytotoxic-differentiation therapy of mouse erythroleukemia cells with 5-fluorouracil and hexamethylene bisacetamide.
The effects of 5-fluorouracil (5-FUra), in combination with various differentiation inducers on the growth and differentiation of mouse erythroleukemia (MEL) cells were investigated. The cells were first treated with 5-FUra, washed, and then treated with various concentrations of differentiation inducers: hexamethylene bisacetamide (HMBA), dimethyl sulfoxide (DMSO), and N-methylformamide. Pretr...
متن کاملDifferentiation inducers modulate cytokine signaling pathways in a murine erythroleukemia cell line.
Hexamethylenebisacetamide (HMBA) is a potent differentiation inducer of murine erythroleukemia cells. Immunoprecipitation followed by Western blotting with an anti-phosphotyrosine (P-Tyr) antibody revealed that HMBA increased P-Tyr levels and/or amounts of several proteins containing P-Tyr in F5-5, a murine erythroleukemia cell line. Among these proteins, we identified a Mr 130,000 protein to b...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Bioorganic & medicinal chemistry letters
دوره 24 5 شماره
صفحات -
تاریخ انتشار 2014