廖高鴻，曾正英，陳國(guó)良

(沈陽(yáng)藥科大學(xué) 基于靶點(diǎn)的藥物設(shè)計(jì)與研究教育部重點(diǎn)實(shí)驗(yàn)室，遼寧 沈陽(yáng)110016)

·綜述與專論· REVIEW AND MONOGRAPH

小分子Janus激酶抑制劑的研究與開發(fā)

廖高鴻，曾正英，陳國(guó)良*

(沈陽(yáng)藥科大學(xué) 基于靶點(diǎn)的藥物設(shè)計(jì)與研究教育部重點(diǎn)實(shí)驗(yàn)室，遼寧 沈陽(yáng)110016)

近年來(lái)的研究發(fā)現(xiàn)，Janus激酶(JAK)可通過(guò)JAK-STAT信號(hào)通路對(duì)細(xì)胞增殖、分化、凋亡以及血管生成、免疫調(diào)節(jié)等起重要作用，其抑制劑可用于骨髓纖維化、惡性腫瘤以及自身免疫性疾病的防治。簡(jiǎn)介JAK-STAT通路與JAK2V617F突變，分類綜述用于治療惡性血液病和腫瘤以及自身免疫性疾病與移植排斥反應(yīng)的小分子JAK抑制劑的研究與開發(fā)。

Janus激酶；JAK-STAT信號(hào)通路；Janus激酶抑制劑；腫瘤；自身免疫性疾病

2005年有4個(gè)研究小組稱，在Ph陰性骨髓增生性腫瘤（Ph-negative MPN)、真性紅細(xì)胞增多癥（polycythemia vera, PV）、原發(fā)性血小板增多癥(essential thrombocythemia, ET)以及骨髓纖維化(myelofibrosis, MF)患者體內(nèi)發(fā)現(xiàn)了新的Janus激酶（JAK）等位基因突變即JAK2V617F突變，這種突變能誘導(dǎo)激活JAK[1-4]。這一發(fā)現(xiàn)不但為上述疾病的病理生理特征研究提供了新的切入點(diǎn)，而且也使JAK成為可能更有效的治療靶點(diǎn)[5]。JAK是一重要的藥物靶點(diǎn)，最初JAK抑制劑被用于治療MF這種罕見的惡性血液疾病[6]，隨后進(jìn)一步的研究發(fā)現(xiàn)JAK抑制劑在惡性腫瘤和常見的自身免疫性疾病治療領(lǐng)域具有良好的應(yīng)用前景，這也是目前小分子JAK抑制劑研發(fā)的兩大方向。

1 JAK-STAT通路與JAK2V617F突變

1.1 JAK-STAT通路

JAK-信號(hào)傳導(dǎo)及轉(zhuǎn)錄激活因子(signal transduction and activators of transcripition, STAT)通路是細(xì)胞因子信號(hào)傳導(dǎo)的重要途徑(見圖1)，可由多種細(xì)胞因子、生長(zhǎng)因子以及受體激活，參與細(xì)胞增殖、分化、凋亡以及血管生成、免疫調(diào)節(jié)等過(guò)程，在腫瘤的發(fā)生、發(fā)展中起重要作用[7]。迄今，在哺乳動(dòng)物體內(nèi)共發(fā)現(xiàn)4個(gè)JAK家族成員(JAK1、JAK2、JAK3及TYK2)以及7個(gè)STAT家族成員(STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b及STAT6)。

圖1 JAK-STAT通路示意圖Figure 1 Diagram of JAK-STAT pathway

由圖1可見，細(xì)胞因子或生長(zhǎng)因子與細(xì)胞膜上受體結(jié)合后，這些受體首先形成同源或異源二聚體，使胞質(zhì)內(nèi)JAK發(fā)生聚集，緊接著鄰近的JAK相互磷酸化而被激活，且促使受體上酪氨酸位點(diǎn)磷酸化而產(chǎn)生與STAT結(jié)合的區(qū)域，然后JAK接近STAT，并使STAT上一個(gè)羥基酪氨酸磷酸化，從而激活STAT，最后活化的STAT與受體分離，形成二聚體，轉(zhuǎn)位至胞核，與特定的DNA片段結(jié)合，調(diào)控基因轉(zhuǎn)錄[8]。正常細(xì)胞中STAT的激活是快速而短暫的，而在腫瘤細(xì)胞中，STAT呈持續(xù)性激活，導(dǎo)致與細(xì)胞增殖、分化、凋亡、侵襲與轉(zhuǎn)移以及血管生成等密切相關(guān)的基因表達(dá)異常[9-10]。因此，抑制JAK-STAT通路，即可抑制STAT的激活，進(jìn)而調(diào)控腫瘤細(xì)胞中異?；虻谋磉_(dá)，最終抑制腫瘤細(xì)胞的增殖，促進(jìn)其凋亡。

1.2 JAK2V617F突變

JAK2V617F突變發(fā)生于JAK2基因的1849位，即原來(lái)的鳥嘌呤(G)被胸腺嘧啶(T)取代，導(dǎo)致原本617位的纈氨酸錯(cuò)譯編碼為苯丙氨酸[11]。目前的諸多研究表明，具有JAK2V617F突變的細(xì)胞中，JAK2及其信號(hào)傳導(dǎo)通路下游的STAT5和蛋白激酶B(Akt)磷酸化水平升高；JAK2V617F突變除了可通過(guò)經(jīng)典的信號(hào)傳導(dǎo)通路激活并增強(qiáng)細(xì)胞因子誘導(dǎo)的信號(hào)級(jí)聯(lián)而調(diào)節(jié)基因表達(dá)，還能通過(guò)非經(jīng)典途徑來(lái)調(diào)節(jié)基因轉(zhuǎn)錄。Dawson等[12]發(fā)現(xiàn)，JAK2存在于人類造血細(xì)胞的細(xì)胞核中，能直接致使組蛋白H3的41位酪氨酸(H3Y41) 磷酸化，而異染色質(zhì)蛋白1A(HP1A)可借助染色體陰影域特異性地結(jié)合于細(xì)胞核內(nèi)組蛋白H3的這一區(qū)域，然后通過(guò)表觀遺傳學(xué)機(jī)制介導(dǎo)基因沉默，由JAK2誘導(dǎo)的H3Y41磷酸化則能阻止這種結(jié)合。另有研究顯示，抑制白血病細(xì)胞中JAK2的活性，能降低H3Y41磷酸化水平，間接促進(jìn)HP1A與組蛋白H3的特異性結(jié)合，最終促使致癌基因沉默[13-15]。

2 用于治療惡性血液病和腫瘤的小分子JAK抑制劑

2.1 已上市或準(zhǔn)備申請(qǐng)上市的相關(guān)藥物

2.1.1 Ruxolitinib Ruxolitinib(1)是美國(guó)Incyte公司開發(fā)的一種選擇性JAK1和JAK2抑制劑，2011年獲美國(guó)FDA批準(zhǔn)，成為首個(gè)專門治療MF的藥物[5]。研究表明，該藥具良好安全性，對(duì)非靶器官無(wú)毒性；且除了對(duì)MF具有顯著療效外，其對(duì)多種血液疾病也有良好的治療作用。臨床研究顯示，MF患者使用該藥治療32個(gè)月后，總生存率達(dá)69%，且經(jīng)該藥長(zhǎng)期治療后，脾腫大癥狀明顯改善[16]。目前，該藥用于原發(fā)性和繼發(fā)性紅細(xì)胞增多癥及ET治療的Ⅲ期臨床研究正在進(jìn)行中，用于繼發(fā)性MPN、急性骨髓性白血病(AML)及銀屑病的治療研究均已進(jìn)入II期臨床試驗(yàn)階段，且用于其他白血病、前列腺癌和多發(fā)性骨髓瘤（MM）的治療也在研究中[17]。臨床研究顯示，18例AML患者接受該藥治療后，3例有明顯的療效反應(yīng)，均達(dá)到完全緩解，且血球計(jì)數(shù)顯著改善[18]。

疾病時(shí)，均能產(chǎn)生良好療效，且并不一定會(huì)造成較大副作用，如多激酶抑制劑對(duì)腫瘤的治療非常有效；而另一方面，雖然目前對(duì)于選擇性JAK抑制劑的作用機(jī)制及療效不甚明確，但高選擇性的JAK1、JAK2、JAK3和TYK2抑制劑可能會(huì)有效減少因作用于其他JAK家族成員而引發(fā)的不良反應(yīng)。因此，選擇性JAK抑制劑已成為目前的研究熱點(diǎn)，且有理由相信，隨著多激酶抑制劑和高選擇性JAK抑制劑研究的不斷深入，其在各類疾病治療領(lǐng)域的應(yīng)用必將更加廣泛。

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Research and Development of Small Molecule Janus Kinase Inhibitors

LIAO Gaohong, ZENG Zhengying, CHEN Guoliang
(Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China)

It has been found in recent years that Janus kinase (JAK) could play a key role on the cellular proliferation, differentiation, and apoptosis as well as angiogenesis and immunoregulation through JAK-STAT signaling pathway, and its inhibitors could be used in the prevention and treatment of myelofibrosis, malignant tumors and autoimmune diseases. JAK-STAT pathway and JAK2V617F mutation were briefly introduced. The research and development of small molecule JAK inhibitors used for the treatment of malignant hempathy, tumors, autoimmune diseases and graft rejection were classifiedly reviewed.

Janus kinase; JAK-STAT signaling pathway; JAK inhibitor; tumor; autoimmune disease

R979.1；R979.5

A

1001-5094（2014）02-0112-08

接受日期：2013-11-20

*通訊作者：陳國(guó)良，教授；

研究方向：抗癌藥物研究；

Tel：024-23986412；E-mail：guoliang222@gmail.com