Wee1抑制剂MK-1775的研究进展

一、        关于Wee1蛋白激酶
        Wee1蛋白激酶是丝氨酸/苏氨酸蛋白激酶家族的一员，最早由Nurse等人在裂殖酵母细胞(S.pombe)中分离出来。由于其可以通过抑制Cdc2的活性来抑制细胞进行有丝分裂，从而使得真核生物体积减小，因而被命名为“Wee”家族。目前，人们对于Wee1蛋白激酶的研究已经不仅仅局限于最初的裂殖酵母，而是相应的扩展到鲫鱼、爪蟾、鼠等多种模式生物，且在人体内，也找到了Wee1的同源基因编码产物。在哺乳动物中，Wee1蛋白激酶家族包括Wee1A、Wee1B和Myt1三个成员，Wee1A在体细胞中表达，Wee1B在胚细胞中表达，Myt1在体细胞和胚细胞中都表达。在人体中，Wee1是一个含有647个氨基酸，且在SDS-PAGE中大小为94 KDa的蛋白质。在其他真核生物中，也可以找到与其功能类似的酶类，但分子大小、结构不尽相同。尽管研究的进程在逐步深入，但对于Wee1蛋白酶的研究，还是以裂殖酵母中最为透彻。

二、        信号通路图

wee信号通路

三、        抑制剂MK-1775
        描述：        MK-1775是一种有效的，选择性Wee1抑制剂，IC50为5.2 nM；抑制G2期DNA损伤检验点。Phase 2.

        体外研究：        MK-1775 inhibits Wee1 kinase in an ATP-competitive manner. Compared to Wee1, MK-1775 displays 2- to 3-fold less potency against Yes with IC50 of 14 nM, 10-fold less potency against seven other kinases with >80% inhibition at 1 μM, and >100-fold selectivity over human Myt 1, another kinase that inhibits cyclin-dependent kinase 1 (CDC2) by phosphorylation at an alternative site (Thr14). By abrogating the DNA damage checkpoint via blockade of Wee1 activity in WiDr cells bearing mutated p53, MK-1775 treatment inhibits the basal phosphorylation of CDC2 at Tyr15 (CDC2Y15) with EC50 of 49 nM, and suppresses gemcitabine-, carboplatin- or cisplatin-induced phosphorylation of CDC2 and cell cycle arrest in a dose-dependent manner, with EC50 of 82 nM and 81 nM, 180 nM and 163 nM, as well as 159 nM and 160 nM, respectively.

        体内研究：        MK-1775 treatment alone at ~20 mg/kg displays minimal antitumor effects against WiDr xenografts in rats with T/C of 69% at day 3. Antitumor efficacy by MK-1775 alone in the nude rat HeLa-luc and TOV21G-shp53 xenograft models models is also moderate