Wee1激酶是參與細胞周期G₂/M檢查點和DNA損傷修復(fù)過程的關(guān)鍵激酶。超過50%的腫瘤存在p53基因缺失或突變，導(dǎo)致細胞周期G₁/S檢查點的缺陷，使得腫瘤細胞DNA的復(fù)制及損傷修復(fù)過程更依賴于G₂/M檢查點。抑制Wee1激酶活性后，腫瘤細胞的DNA損傷不能及時修復(fù)便進入M期，造成基因組不穩(wěn)定性和染色體缺失，引發(fā)有絲分裂災(zāi)難，導(dǎo)致腫瘤細胞凋亡。adavosertib是阿斯利康公司研發(fā)的小分子選擇性Wee1激酶抑制劑，通過選擇性抑制Wee1激酶，阻滯p53基因缺陷型腫瘤在G₂/M期檢查點的DNA損傷修復(fù)，導(dǎo)致腫瘤細胞死亡，最終達到治療腫瘤的目的。目前adavosertib單用或與其他抗癌藥物聯(lián)合的研究正處于I/Ⅱ期臨床研究中，其有效性和安全性已經(jīng)得到驗證。

Wee1 is the key kinase in cell cycle G₂/M check point and DNA damage repair. P53 gene mutates in more than 50% of tumor cells and abrogates the G₁/S phase check point in cell cycle, which makes it more dependent on G₂/M check point. Once Wee1 is inhibited, tumor cell cycle enters M phase without repairing DNA damage timely. It causes genomic instability and chromosomal deletion, induces mitotic catastrophe and leads to the apoptosis of tumor cells. adavosertib is a kind of selective small molecule Wee1 inhibitors launched by AstraZeneca. adavosertib retards DNA damage repair of p53 mutated tumor cells on G₂/M check point, leads to the death of tumor, and achieves the goal of cancer treatment. At present, the phase I/Ⅱ clinical trials of adavosertib`s monotherapy and combination therapy with other anti-tumor drugs are in progress and its effectiveness and safety have been confirmed.

中國醫(yī)學科學院醫(yī)學與健康科技創(chuàng)新工程經(jīng)費資助項目（2016-I2M-3-022、2017-I2M-2-019）