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嘧啶并吡啶酮骨架作为新型蛋白激酶小分子抑制剂的设计、合成及生物活性研究
Alternative TitleDesign, Synthesis and Bioactivity Study of Pyrido[2,3-d]pyrimidine-7-one Small Molecules as New Kinase Protein Inhibitors
余蕾
Subtype博士
Thesis Advisor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嘧啶并吡啶酮类 非小细胞肺癌 不可逆抑制剂 选择性抑制剂 EGFRT790M Mps1/ TTK
Abstract蛋白激酶是细胞生命活动重要的信号使者,通过催化底物磷酸化,控制细胞的信号转导,参与调控细胞增殖、存活、凋亡、代谢、转录和分化等生理活动。药理学及病理学研究表明,蛋白激酶对于很多疾病均是很理想的药物靶点。近十几年来,自从第一个激酶类小分子药物伊马替尼被批准上市,陆续有各种不同骨架类型的激酶小分子抑制剂被批准进入临床治疗。如EGFR抑制剂吉非替尼、Raf抑制剂索拉菲尼、BTK抑制剂依鲁替尼、CDK4/ 6抑制剂帕博替尼等。本课题组靶向蛋白激酶进行各种小分子药物的开发,本论文主要基于嘧啶并吡啶酮骨架,针对表皮生长因子受体(EGFR)和单极纺锤体1(Mps1/ TTK)进行合理药物设计和开发。本课题组前期已经开发得到了一类嘧啶并吡啶酮化合物(1-19),该化合物表现出良好的EGFR激酶活性和选择性,但是较差的药代动力学性质(口服生物利用度10 %)限制了其进一步开发。为了改善药代动力学性质,本文第一章在保留嘧啶并吡啶酮骨架的基础上对化合物的左支和右支侧链进行了一系列构效优化。其中化合物1-20aa和1-20ah可以有效抑制EGFR激酶活性和H1975细胞增殖,并且在大鼠体内的口服生物利用度分别提高到了24.9 %和16 %。在小鼠体内H1975细胞移植瘤实验中,1-20aa以50 mg/ kg每天一次口服给药时,可以有效抑制移植瘤的增长。我们的研究有效地改善了嘧啶并吡啶酮类化合物的药代动力学性质,为开发第三代EGFRT790M选择性不可逆抑制剂提供了重要的候选分子。本论文第二章通过对嘧啶并吡啶酮骨架小分子进行激酶谱筛选,得到了苗头化合物2-25a,该化合物在468种激酶筛选中仅对包括Mps1在内的5种激酶有较强抑制作用。对比已经报道的选择性Mps1小分子抑制剂,该化合物表现出了更高的激酶选择性,因此本文第二章通过骨架跃迁和姘合、生物电子等排等修饰手段,对苗头化合物进行了一系列的结构优化。构效关系修饰发现,当连接环linker和尾部基团分别为顺式1,4-环己二胺连接环和三甲基乙酰氨基时,化合物对Mps1激酶具有较好的抑制活性,化合物2-25q对Mps1的激酶活性达到了0.151 μM。当头部骨架的R1为体积较小的H取代时活性较优,2-25x对Mps1的激酶抑制活性为0.127 μM。这几个化合物正在进行各类生物活性的评估,而进一步关于头部和左支侧链的构效关系研究正在进行中,期望能够通过构效优化得到生物活性和选择性以及药代动力学性质较优的候选药物分子。
Other AbstractProtein kinases are important signal messengers in cell life. They mediate most of the signal transduction in eukaryotic cells by modification of substrate activity. Protein kinases also control many other cellular processes, including metabolism, transcription, cell cycle progression, cytoskeletal rearrangement and cell movement, apoptosis, and differentiation. Many pharmacological and pathological research have indicated that protein kinases are important targets for drug development. Since imatinib has been approved, more and more small-molecule inhibitors targeting protein kinases have come into market, e.g. EGFR inhibitor gefitinib, Raf kinase inhibitor sorafenib, BTK inhibitor ibrutinib and CDK4/ 6 inhibitor palbociclib, etc.. Inspired by these successful development, our group have designed and synthesized a serials of protein kinase inhibitors. This dissertation mainly focused on rational design and synthesis of epidermal growth factor receptor (EGFR) and monopolar spindle 1 (Mps1/ TTK) inhibitors based on the pyrido[2,3-d]pyrimidine-7-one scaffold. Our group had explored great efforts to discover novel EGFRT790M mutant selective inhibitors with pyrido[2,3-d]pyrimidine-7-one scaffold. The lead compound (1-19) displayed potent and specific EGFRT790M inhibition. However, it possessed unacceptable pharmacokinetic (PK) parameters such as poor oral bioavailability (F= 10 %) which limit the further development. In chapter 1, we describe further structural optimization of the lead compound with an aim of improving its PK profiles. Two of the most promising compound 1-20aa and 1-20ah potently inhibited EGFR kinase and suppressed the proliferation of H1975 cells. They also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 24.9 % and 16 %, respectively. Furthermore, 1-20aa displayed promising antitumor efficacy in vivo in an EGFRL858R/T790M-driven human H1975 xenograft model without obvious toxic signs during treatment. Our study provide a promising candidate compound with improved pharmacokinetic properties and acceptable in vivo antitumor efficacy for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients. In chapter 2, we identified a pyrido[2,3-d]pyrimidin-7-one derivative as Mps1/ TTK hit compound through kinase profile screening from our compound library. The hit showed reasonable selectivity against a panel of 468 human kinases at 100 nM and there were only 5 ‘off- target’ kinases. We firstly modified the linker and the tail group of the hit. These effort led to compound 2-25b and 2-25q with IC50 values of 0.255 and 0.151 μM against Mps1 kinase, respectively. The structure-activity relationship showed that the (1s,4s)-cyclohexane-1,4-diamine linker and pivaloyl tail were beneficial to Mps1 kinase activity. Compound 2-25x with a H substitution on R1 position of the core exhibited better Mps1 inhibitory. Inspired by these data, we will make a full structure-activity relationship (SAR) study on the head site and side chain to afford good candidates for cancer therapy.
Subject Area药物化学
Pages229
Language中文
Document Type学位论文
Identifierhttp://ir.foo.ac.cn/handle/2SETSVCV/1137
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
余蕾. 嘧啶并吡啶酮骨架作为新型蛋白激酶小分子抑制剂的设计、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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