可同时抑制罕见白血病及前列腺癌的新型化合物

  近日，来自密歇根大学综合癌症研究中心的研究人员通过研究开发了一种新型药物，实验室研究中该药物可潜在抵御一种罕见的急性白血病，而在另外一项研究中研究者也发现相同的化合物在前列腺癌疗法中扮演着重要角色，相关研究结果分别发表于国际杂志Cancer Cell和Nature Medicine上。

  研究者Jolanta Grembecka表示，这种化合物是在我们实验室开发出来的，研究者通过很多年研究鉴别出了这种小分子抑制剂，其可以阻断诱发罕见急性白血病的menin蛋白和MLL融合蛋白之间的相互作用。这种名为MLL融合白血病的急性白血病在成年个体和幼儿中均可发生，其在成年白血病个体中大约占10%，而在婴儿白血病中大约占到了70%，当前的疗法并没有效果，而且仅有三分之一的病人存活期超过了5年。

  蛋白和蛋白间的相互作用，比如白血病中menin-MLL融合蛋白之间的相互作用普遍被认为是无法用药物控制的，这就意味着开发新型药物靶向作用其二者之间的相互作用非常具有挑战性；研究者表示，在很多癌症中，你会看到多种相互作用和突变会诱发癌症，menin-MLL之间的相互作用是一种较好的药物靶点，因为其是白血病的原始诱发子，通过阻断这二者之间的反应或许就可以阻断癌症的发生。

  发表在Cancer Cell上的这篇研究论文中，研究者在MLL白血病的小鼠和细胞系中检测了两种化合物：MI-463和MI-503的作用，结果显示，这两种化合物均可以在不损伤正常血细胞的情况下来阻断menin-MLL之间的作用；而且这两种化合物也可以在血液中进行运输并且可以以一个很好的比例被代谢掉。

  与此同时，发表在国际杂志Nture Medicine上研究论文中，研究者检测了相同的menin-MLL的抑制剂对去势耐药性前列腺癌细胞的作用效率，结果表明，这两种化合物在抑制常见实体瘤中扮演着重要角色，比如前列腺癌；研究者表示，在这种新型化合物进入临床试验之间应当在实验室对其安全性进行检测，后期研究者将调查MLL在去势抵抗性前列腺癌中的作用，研究者希望通过他们的研究或可开发出治疗前列腺癌的新型疗法。（转化医学网360zhyx.com）

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转化医学网推荐的原文摘要：

Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo
Cancer Cell DOI: 10.1016/j.ccell.2015.02.016
Dmitry Borkin1, 13, Shihan He1, 13, Hongzhi Miao1, 13, Katarzyna Kempinska1, Jonathan Pollock1, 2, Jennifer Chase3, 4, Trupta Purohit1, Bhavna Malik1, Ting Zhao5, Jingya Wang1, 12, Bo Wen5, Hongliang Zong9, Morgan Jones3, 4, 6, Gwenn Danet-Desnoyers10, Monica L. Guzman9, Moshe Talpaz7, Dale L. Bixby7, Duxin Sun5, Jay L. Hess1, 11, Andrew G. Muntean1, Ivan Maillard3, 7, 8, Tomasz Cierpicki1, Jolanta Grembecka1, ,
Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.

Targeting the MLL complex in castration-resistant prostate cancer
Nature Medicine doi:10.1038/nm.3830
Rohit Malik, Amjad P Khan, Irfan A Asangani, Marcin Cieślik, John R Prensner, Xiaoju Wang, Matthew K Iyer, Xia Jiang, Dmitry Borkin, June Escara-Wilke, Rachell Stender, Yi-Mi Wu, Yashar S Niknafs, Xiaojun Jing, Yuanyuan Qiao, Nallasivam Palanisamy, Lakshmi P Kunju, Pranathi M Krishnamurthy, Anastasia K Yocum, Dattatreya Mellacheruvu, Alexey I Nesvizhskii, Xuhong Cao, Saravana M Dhanasekaran, Felix Y Feng, Jolanta Grembecka et al.
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion–positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin–MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin–MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.