开题报告内容：（包括拟研究或解决的问题、采用的研究手段及文献综述，不少于2000字）
1. Background of the Study
1.1 Introduction to Target Anticancer Therapeutics and its Target Selection
Although significant improvements in healthcare has been made in the past decades, tumor-related diseases remain the second leading cause of death worldwide. Especially in China, the number of malignant tumors rank first in the world according to China Malignant Tumor Development Report. Intensive research has been conducted in order to discover an effective treatment for tumor-related diseases in recent years. In the early era of drug discovery, the chemotherapy has been the spotlight; however due to its side effects and resistance problems, target anticancer approach has become a promising solution to anticancer therapeutics. Kinase inhibitors among them emerged as one of the most successful approaches and many inhibitors of this kind have been approved by the FDA in recent years, proving its potential as the key to target anticancer therapy. However, it also faces challenges in off-target effects and resistance problems. Since these target kinases are expressed widely in human body, off-target issue must be solved, and growing resistance by repeated use must be managed in order to have these inhibitors advance to clinical use. Many strategies have been made to overcome such challenges; it has been discovered lately that a new approach for interfering with DNA synthesis through targeting UCK2, which is vary in other drugs mechanism of treating tumor.
1.2 Introduction of UCK2
Nucleotides serves as the foundation in all cellular metabolic process, especially for tumor cells. In the tumor cells, imbalances of nucleosides induce tumor cells proliferation and growth without limitation. Compared to normal cells, tumor cells need more nucleotides to enrich themselves. During tumor cells proliferation, the synthesis rate of DNA and RNA increases with the increasing amount of substrates. After that, the constant turnover of RNA arises both during their production and the amounts of mRNA regulated for protein synthesis. Among the whole process, UCK plays an important role in it. Uridine-cytidine kinase (UCK) is a rate-limiting enzyme playing an essential role in synthesizing both RNA and DNA2. It participates in the phosphorylation process of uridine and cytidine, responsible for attaching a phosphate group to the pyrimidine nucleoside, which is the first step in the synthesis of pyrimidine nucleoside triphosphates. UCK2 is crucial to many nucleoside antimetabolites, important chemotherapeutic agents used in clinic, since UCK2 also engage in exerting these agentsrsquo; pharmacological actions. Only after phosphorylation of ribonucleoside analogs, they can act as cytotoxic drugs. There are two forms UCK existing in the human body, namely UCK1 and UCK2. Although they have about 69% sequence identity in common, the expression range is different. UCK1 is ubiquitously expressed in many tissue and organs such as liver, kidney and so on. However, most of the UCK2 are found in cancerous cells and healthy placental tissue3. Apart from that, catalytic ability of UCK2 is much more effective than UCK1 and instead of UCK1, the level of UCK2 is related to the cellular sensitivity of ribonucleotide analogue. Therefore, it is more common to detect overexpression of UCK2 than UCK1 in tumor cells, indicating that the expression of UCK2 is associated with tumor4. The fact that UCK2 overexpression in tumor cells shows that it may become a promising antitumor target. Moreover, the expression of UCK2 is low in normal tissue, which is beneficial to control the dose of the inhibitor. Rather than protein kinases, targeting synthesis of RNA and DNA can avoid mutation in target protein. Nucleoside analogs can incorporate into RNA and DNA through mimicking the structure of the substrate. With that aim, the project is to design and synthesize potential UCK2 inhibitors, nucleoside analogs, in order to find a new target for tumor treatment.
1.3 Structure of human UCK2
UCK2 is a tetramer enzyme in the pyrimidine-nucleotide salvage pathway. The tetramer is made up of two molecules in the ASU and another two molecules in crystallographic symmetry. UCK2 monomer has a core five-stranded parallel beta;-sheet flanked on both sides by a pair of alpha;-helices. In the structure of UCK2 monomer, altogether there are 12 hydrogen bonds between the side chains of UCK2 and the CMP molecule, which may be the reason why UCK2 can catalyze substrate effectively. Among these 12 hydrogen bonds, His117 and Tyr112 are responsible for generating hydrogen bonds with cytosine and uracil bases in the structure of nucleosides. Asp84 and Arg166 engage in forming hydrogen bonds with the 2rsquo;-and 3rsquo;-hydroxyl groups of the ribose. Moreover, Asp62 is a crucial acidic residue responsible for activating substrate, triggering 5rsquo;-hydroxyl group to attack the phosphorus group of the ATP. In the process of phosphorylation, Asp62 changes its conformation to better fit the sugar part of the nucleoside5. Apart from these hydrogen bonds between UCK2 and substrate, the active sites of UCK2 also contains one magnesium ion. The present contribution reports the rapid crystal structure determination of human UCK2 complexed with a magnesium ion and the reaction products adenosine 5rsquo;-diphosphate(ADP) and CMP.
2. Design of Potential UCK2 Inhibitors: Lead Compound and Rationale
Cytidine analogs belongs to nucleoside analogs taking place of cytidine to incorporate into RNA and DNA. In this way, cytidine analogs can treat a wide range of cancer types. Among them, compound RX 3117 is a ribonucleotide analogue which is in phase 2 clinical trials for the treatment of pancreatic cancer. 6 The mechanism revealed thus far indicates that the compound shows biological activity by inhibiting the UCK2. In this regard, the RX3117 is considered the lead compound in designing potential UCK2 inhibitors.
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