- 學位論文
以藥物誘發胎兒血紅素治療重症鐮刀型貧血與β型地中海型貧血
Pharmacological induction of HbF for treating severe sickle cell disease and β-thalassemia
摘要
利用治療藥物誘發胎兒血紅素再表現已被建議做為治療重症鐮刀型貧血或β型地中海型貧血等貧血的替代療法。Hydroxyurea (HU)是第一個通過美國FDA核可用來治療鐮刀型貧血的胎兒血紅素誘發藥物。然而HU對25%的病人無效。在本實驗室之前的研究中已發現數個具有相同藥效基團的化合物可以誘發胎兒血紅素再表現，但由於不佳的水溶性和生物吸收效率限制了往臨床使用的發展性。為了研發出可作為藥物使用的化合物，我們進一步的探討其結構和活性之間的關係。在本篇研究中我們分成了兩個系列的化合物進行研究。我和中研院生醫所的蘇燦隆老師合作合成了系列一的化合物，SS-2394是被挑選進一步研究的候選化合物。在之前的研究中已經了解了SS-2394誘發胎兒血紅素的效果以及其作用機制，在此我進一步利用IPA去探討其對細胞的整體影響。同時利用β-YAC基因轉殖小鼠和鐮刀型貧血小鼠測試SS-2394在體內的作用效果。另一方面我和國衛院的蔣維棠老師合作，利用之前已被報導過的胎兒血紅素誘發化合物TN1和Compound II的結構合成了93個系列二的新化合物。在此我們揭露系列二中更為有效的化合物AS-28，可以在無細胞毒性的濃度下有效誘發胎兒血紅素的表現。我也探討了AS-28的作用機制以及利用IPA分析其對細胞的整體影響。此外口服餵食AS-28給鐮刀型貧血症的小鼠可以減緩貧血和其他相關症狀。本論文研究結果顯示AS-28有潛力發展成新一代治療重症鐮刀型貧血以及β型地中海型貧血的新藥。
並列摘要
Reactivation of fetal hemoglobin (HbF) expression by therapeutic agents has been suggested as an alternative strategy to modulate anemia, such as symptoms of severe β-thalassemia and sickle cell disease (SCD). Hydroxyurea (HU) is the first US FDA-approved HbF inducer for treating SCD. However, approximately 25% of the patients with SCD have no response to HU. In our previous study, we found several compounds bearing same pharmacophore can induce HbF. However the poor solubility and bioavailability limit the development of these inducers for clinical use. To develop drug-like compounds, further structure-activity relationship studies were conducted. In my thesis, I studies two classes of compounds. Class 1 compound, in cooperation with Dr. Tsann-Long Su in IBMS, Academia Sinica, SS-2394 is the candidate compound, in which HbF induction ability and molecular mechanisms had been revealed in previous study. In this study, I further investigate the global effect of SS-2394 by Ingenuity Pathway Analysis (IPA). The in vivo efficacy of SS-2394 in β-YAC transgenic mice and SCD mice were evaluated. The other compounds categorized as Class 2 compound were from Dr. Weir-Torn Jiaang in NHRI, who synthesized 93 new compounds based on the structure of previous studies, and identified as HbF inducer, TN1 and compound II. Herein, I found a more potent inducer from class 2, compound AS-28. It can efficiently induce HbF expression at non-cytotoxic concentrations. The molecular mechanisms of AS-28 for regulation of HbF expression was also investigated. The global effects of AS-28 were also applied for IPA. In addition, we demonstrated that oral administration of AS-28 can ameliorate anemia and the related symptoms in sickle cell disease mice. The results of this study suggest that AS-28 can be further developed as a novel agent for treating hemoglobinopathies, such as severe β-thalassemia and sickle cell disease.
參考文獻
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