Identification of a Small Molecule That Overcomes HdmX-Mediated Suppression of p53.
Identification of a Small Molecule That Overcomes HdmX-Mediated Suppression of p53.
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DOI：
10.1158/1535-7163.mct-15-0467
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发表时间：
2016-04
影响因子：
5.7
通讯作者：
Wald DN
中科院分区：
文献类型：
--
作者：
Karan G;Wang H;Chakrabarti A;Karan S;Liu Z;Xia Z;Gundluru M;Moreton S;Saunthararajah Y;Jackson MW;Agarwal MK;Wald DN
p53肿瘤抑制因子因突变或负调控因子过表达而失活在癌症中经常发生。由于p53在DNA损伤化疗的增殖或凋亡调控中起着关键作用，旨在重新激活p53的策略正越来越多地被寻求。重新激活野生型p53的策略包括使用能够从关键的细胞负调节因子（如Hdm2和HdmX）中释放野生型p53的小分子。Hdm2拮抗剂Nutlin-3的衍生物正在临床试验中。然而，Nutlin-3特异性地破坏Hdm2-p53，使肿瘤中含有高水平的HdmX对Nutlin-3治疗产生抗性。在这里，我们鉴定了CTX1，一种克服hdmx介导的p53抑制的新型小分子。CTX1直接与HdmX结合，阻止p53-HdmX复合物的形成，从而以DNA损伤无关的方式快速诱导p53。用CTX1治疗一组癌细胞诱导细胞凋亡或抑制增殖，重要的是，CTX1在循环原发性人类白血病小鼠模型中显示出有希望的单药活性。CTX1是一种小分子HdmX抑制剂，有望成为癌症治疗的候选药物。
Inactivation of the p53 tumor suppressor by mutation or overexpression of negative regulators occurs frequently in cancer. Since p53 plays a key role in regulating proliferation or apoptosis in response to DNA damaging chemotherapies, strategies aimed at reactivating p53 are increasingly being sought. Strategies to reactivate wild-type p53 include the use of small molecules capable of releasing wild-type p53 from key, cellular negative regulators, such as Hdm2 and HdmX. Derivatives of the Hdm2 antagonist Nutlin-3 are in clinical trials. However, Nutlin-3 specifically disrupts Hdm2-p53, leaving tumors harboring high levels of HdmX resistant to Nutlin-3 treatment. Here we identify CTX1, a novel small molecule that overcomes HdmX-mediated p53 repression. CTX1 binds directly to HdmX to prevent p53-HdmX complex formation, resulting in the rapidly induction of p53 in a DNA damage-independent manner. Treatment of a panel of cancer cells with CTX1 induced apoptosis or suppressed proliferation and importantly, CTX1 demonstrates promising activity as a single agent in a mouse model of circulating primary human leukemia. CTX1 is a small molecule HdmX inhibitor that demonstrates promise as a cancer therapeutic candidate.