【摘要】：Polo樣激酶(polo-like kinase, Plk)是一類廣泛存在于真核生物中的絲氨酸/蘇氨酸蛋白激酶。其中,Plkl調(diào)控細(xì)胞有絲分裂多個(gè)環(huán)節(jié),在80%人類腫瘤細(xì)胞中過(guò)度表達(dá),包括乳腺癌、結(jié)腸直腸癌、前列腺癌、胰腺癌、非小細(xì)胞肺癌、卵巢癌等,但在正常組織中很少表達(dá)。抑制Plkl的活性可以產(chǎn)生良好的抗癌效果,因而Plkl是一個(gè)很好的抗腫瘤藥物研發(fā)的靶點(diǎn)。目前,已有眾多Plkl小分子靶向抑制劑被報(bào)道,但仍存在著Plk家族內(nèi)部選擇性差、藥代動(dòng)力學(xué)方面的諸多問(wèn)題,開發(fā)特異性、可口服的Plkl抑制劑因此至關(guān)重要。本研究采用基于結(jié)構(gòu)的藥物設(shè)計(jì)理論,以首個(gè)進(jìn)入臨床實(shí)驗(yàn)的Plkl抑制劑BI2536為先導(dǎo)化合物,保留其核心藥效團(tuán)骨架,利用家族內(nèi)部氨基酸殘基的細(xì)微差異,進(jìn)行特異性的結(jié)構(gòu)修飾從而達(dá)到提高活性與選擇性的目的,再利用計(jì)算機(jī)輔助軟件進(jìn)行虛擬評(píng)價(jià),設(shè)計(jì)并合成了27個(gè)結(jié)構(gòu)新穎的全新化合物。最后,采用體外激酶抑制實(shí)驗(yàn)與抗腫瘤細(xì)胞株實(shí)驗(yàn)對(duì)化合物進(jìn)行生物學(xué)評(píng)價(jià)。測(cè)試結(jié)果表明,所設(shè)計(jì)的大部分化合物均對(duì)Plkl產(chǎn)生了低納摩爾濃度的抑制活性以及家族內(nèi)部的選擇性。其中化合物C2對(duì)Plkl的ICso值達(dá)到了4.134 nM,優(yōu)于陽(yáng)性對(duì)照物BI2536和十字孢堿,并且將家族內(nèi)部Plk2、Plk3的選擇性分別提高至54倍和35倍。同時(shí)該化合物對(duì)體外MCF-7、K562、Hela癌細(xì)胞株的抑制活性分別為40.69 nM、41.67 nM、37.71 nM,同樣優(yōu)于陽(yáng)性對(duì)照物BI 2536與紫杉醇。本課題初步篩選出了一系列高效、低毒、結(jié)構(gòu)新穎的Plkl抑制劑,為進(jìn)一步開發(fā)新型高效的抗癌藥物奠定了基礎(chǔ)。
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圖片說(shuō)明：圖１．２邐（ａ）抑制劑與ＮＣＤ邋口袋的結(jié)合模式；（ｂ）抑制劑與ＰＢＤ邋口袋的結(jié)合模式逡逑Ｆｉｕｒｅ邋１．２ａＴｈｅ邋ｂｉｎｄｉｎｍｏｄｅ邋ｏｆ邋ｉｎｈ化ｉｏｒ邋ｗｉｈ邋化ｅ邋ＮＣＤｂＴｈｅ邋ｂｉｎｄｉｎｍｏｄｅ邋ｏｆ邋ｉｎｈ化ｉｔｏｒ邋ｗｉｔｈ逡逑
[Abstract]:Polo-like kinase (polo-like kinase, Plk) is a kind of serine / threonine protein kinase which widely exists in eukaryotes. Among them, Plkl regulates mitosis and is overexpressed in 80% of human tumor cells, including breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, non-small cell lung cancer, ovarian cancer and so on, but rarely expressed in normal tissues. Inhibition of Plkl activity can produce good anticancer effect, so Plkl is a good target for antitumor drug development. At present, many Plkl small molecule targeting inhibitors have been reported, but there are still many problems in Plk family, such as poor selectivity and pharmacokinetics. It is very important to develop specific and oral Plkl inhibitors. In this study, the structure-based drug design theory was used, the first Plkl inhibitor BI2536, which entered the clinical trial, was used as the lead compound to retain its core pharmacophore skeleton, and the specific structure modification was carried out by using the nuances of amino acid residues within the family to improve the activity and selectivity. 27 new compounds with novel structure were designed and synthesized by virtual evaluation with computer-aided software. Finally, the biological evaluation of the compounds was carried out by in vitro kinase inhibition test and anti-tumor cell line test. The results showed that most of the compounds produced low nanomolconcentration inhibitory activity and intra-family selectivity to Plkl. The ICSO value of compound C2 to Plkl was 4.134 nM, which was better than that of BI2536 and Cruciferine, and the selectivity of Plk2,Plk3 in the family was 54 times and 35 times, respectively. At the same time, the inhibitory activity of the compound on MCF-7,K562,Hela cell line in vitro was 40.69 nM,41.67 nM,37.71 nM, which was also better than that of BI 2536 and paclitaxel, respectively. In this paper, a series of Plkl inhibitors with high efficiency, low toxicity and novel structure were screened out, which laid a foundation for the further development of new and efficient anticancer drugs.
【學(xué)位授予單位】：合肥工業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R914;R96

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