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选择性FGFR不可逆抑制剂及其低氧激活型前药的设计、合成及生物活性研究
Alternative TitleDesign, Synthesis and Biological Evaluation of of Selective Irreversible FGFR Inhibitors and their Hypoxia-activated Prodrugs
李学强
Subtype博士
Thesis Advisor许永 ; 丁克
2017-05-01
Degree Grantor中国科学院大学
Place of Conferral广州生物院
Degree Name理学博士
Degree Discipline药物化学
Keyword低氧 成纤维生长因子受体 不可逆抑制剂 低氧激活型前药
AbstractFGFR是成纤维细胞生长因子受体,其在细胞信号的传递过程中起着重要的作用。FGFR的异常表达与多种实体瘤的发生、发展密切相关。FGFR已经成为癌症治疗的新靶点。现有FGFR小分子抑制剂,由于缺乏肿瘤靶向性,能抑制人体正常组织中的FGFR,导致毒副作用大,限制了其在临床上的使用。低氧是实体肿瘤的常见特征之一,也是引起肿瘤对放疗、化疗产生耐受,导致肿瘤耐药、复发、侵袭和转移的重要原因。肿瘤低氧已成为肿瘤药物治疗的一个重要靶点。低氧激活前药是一类对正常组织无毒或毒性较低、进入肿瘤低氧微环境后即可被激活并发挥抗肿瘤活性的药物。这种低氧激活前药策略已被应用于多个细胞毒性药物的研究中,并获得了很好的效果;但利用这种策略来解决FGFR抑制剂的毒副作用问题,尚未见报到。首先,我们设计并合成了一系列新型嘧啶并嘧啶酮和嘧啶并吡啶酮类FGFR抑制剂。代表性化合物1-29l对FGFR1-4激酶的抑制活性IC50值分别为1.06、0.84、5.38和68.7 nM;能有效抑制FGFR依赖的H520、SUM52和SW780细胞的增殖(IC50值分别为4.14、0.65和9.73 nM);而对非FGFR依赖的肿瘤细胞和人正常肝细胞HL7702的抑制活性在微摩尔水平。而且,1-29l在30 nM浓度下能完全抑制FGFR2扩增的SUM52细胞中FGFR2和下游蛋白ERK1/2的磷酸化。此外,洗脱实验证实化合物1-29l能以不可逆的方式作用于FGFR1-3激酶。随后,我们将低氧激活型药效团引入到上述FGFR抑制剂的母核中,设计并合成了11个低氧激活型FGFR抑制剂。代表性前药1-47的最大耐受剂量为133 mmol/kg,且耐受性良好;在小鼠膀胱癌细胞SW780和胃癌细胞SNU16的移植瘤模型中,1-47能有效抑制肿瘤生长,且小鼠体重无明显变化。本研究发现的低氧诱导激活FGFR抑制剂,为开发新型肿瘤靶向型FGFR抑制剂治疗癌症患者提供了重要的候选化合物。
Other AbstractAfter being activated by fibroblast growth factor (FGF) ligands, the FGFR family regulates many key biological processes. FGFR aberrations are identified in a variety of human cancers. Thus, the FGFR family members have become promising molecular targets for new anticancer drug development. While small molecure FGFR inhibitors show efficacy in patients harboring cancers with deregulated FGFR signaling, severe side effects are also observed due to inhibition of FGFR in human normal tissue which limited their clinical use. Hypoxia is one of the characteristic features of solid tumour biology as a result of an inadequate supply of oxygen. Tumour hypoxia is known to promote the development of tumor cell proliferation, survival, metabolism, metastasis, angiogenesis and the resistance to radio/chemo-therapy which is strongly associated with poor clinical outcome. Therefore, tumor hypoxia has been becoming an important target for cancer therapy. Hypoxia-activated prodrugs ( HAPs),which were nontoxic or low-toxic to normal organisms,while they were active to tumor cells after reaching hypoxia microenvironment,have already become a hot spot of antitumor drugs development. To date, no reports that using HAPs targeting FGFR have been reported. We envisioned that the development of FGFR inhibitors containing hypoxia-activated pharmacophore may selectively exert antitumor activities in hypoxic cells and minimize the side effects. Firstly, we design and synthesize 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl and pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as FGFR inhibitors. One of the most promising compounds 1-29l potently inhibited FGFR1/2/3/4 with IC50 values of 1.06, 0.84, 5.38 and 68.7 nM, respectively. Compound 1-29l strongly suppresses the proliferation of FGFR1-amplified H520 non-small cell lung cancer cells, FGFR2-amplified SUM52 breast cancer cells and FGFR3-amplified SW780 bladder cancer cells with low nanomolar IC50 values, but was significantly less potent against four FGFR-negative cancer cell lines and normal human liver HL7702 cells, with low micromolar IC50 values. Biological investigation also confirmed the irreversible binding of the molecule with the FGFR1-3 target kinases.Lastly, eleven hypoxia-activated FGFR inhibitors were designed and sythesiezd. The representive prodrug 1-47 displayed promising antitumor efficacy in vivo in FGFR2-driven human SNU16 and FGFR3-driven human SW780 xenograft mouse models without significant body loss. The maximum tolerated dose of 1-47 is 133 mmol/kg and without obvious toxic signs were observed during the treatment.Our studies provide a new hypoxia-activated FGFR inhibitor with promising in vivo antitumor activity for further development of the drug targeting FGFR.
Subject Area药物化学
Pages152
Language中文
Document Type学位论文
Identifierhttp://ir.foo.ac.cn/handle/2SETSVCV/1145
Collection中国科学院广州生物医药与健康研究院
Affiliation中国科学院广州生物医药与健康研究院
First Author AffilicationGUANGZHOU INSTITUTES OF BIOMEDICINE AND HEALTH,CHINESE ACADEMY OF SCIENCES
Recommended Citation
GB/T 7714
李学强. 选择性FGFR不可逆抑制剂及其低氧激活型前药的设计、合成及生物活性研究[D]. 广州生物院. 中国科学院大学,2017.
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