Development of Gadd45b-Targeting Agents for Multiple Myeloma Therapy

帝国理工学院的Guido Franzoso教授和他的同事发现了一种治疗多发性骨髓瘤的新方法，这是一种骨髓癌，可以治愈这种疾病。相比之下，现有的药物具有严重的副作用，限制了可以给予的剂量。最新的治疗方法硼替佐米（Velcade）不能杀死所有的癌症，允许一些癌细胞逃逸，虽然疾病可以暂时稳定，但复发是不可避免的。因此，美国、欧洲和日本每年确诊的11万人中的大多数将在3-5年后死亡。这种血液传播的癌症不能使用放射治疗或手术治疗，因此选择仅限于化疗或骨髓移植。我们发现了一种新的蛋白质，称为Gadd 45 b，它形成了细胞之间关键分子连接的一半。一种名为MKK 7的酶控制着第二条信号通路（JNK）的交通，这两种分子结合在一起，阻止了告诉正常骨髓细胞死亡的信号，使它们无法控制地繁殖。我们设计了一些小分子来阻止这两种蛋白质相互结合。与正常骨髓相比，多发性骨髓瘤癌细胞含有高水平的Gadd 45 b，我们已经证明，我们可以通过阻止Gadd 45 b与其配偶体MKK 7结合来杀死实验室中的人类骨髓瘤细胞。我们已经证明，这些蛋白质不？它不会影响正常细胞，使它们成为寻找新药物疗法的有希望的起点。下一步将是找出这些分子在癌症模型中的行为，并利用这些信息创造第二代改进的分子。在这项研究的最后，我们的目标是创造一种化合物，可以在一两年内给予患者。这种治疗方法不仅可以稳定病情，而且实际上可以治愈多发性骨髓瘤。该团队在制药行业拥有丰富的成功药物发现和开发经验，并将使用帝国理工学院开发肽分子。拥有广泛的生物、化学和临床设施。

Professor Guido Franzoso and his colleagues at Imperial College have discovered a new way of tackling multiple myeloma, a cancer of the bone marrow, which could offer a cure for this disease. In contrast, existing drugs have severe side effects that limit the doses that can be given. The most recent treatment, bortezomib (Velcade) cannot kill all of the cancer, allowing some of the cancer cells to escape and, whilst the disease can be temporarily stabilised, relapse is inevitable. As a result, most of the 110,000 people diagnosed each year with the disease in US, Europe and Japan will die about 3-5 years later. This blood borne cancer cannot be treated using radiotherapy or surgery and so the options are restricted to chemotherapy or bone marrow transplant. We have discovered a new protein, called Gadd45b, which forms one half of a crucial molecular link between cells. An enzyme called MKK7 controls traffic in a second signalling pathway (JNK) and, bound together, these two molecules stop the signals that tell normal bone marrow cells to die, allowing them to multiply uncontrollably. We have designed small molecules that prevent the two proteins from binding to one another. Multiple myeloma cancer cells contain high levels of Gadd45b, compared to normal bone marrow, and we have already shown that we can kill human myeloma cells in the laboratory by preventing Gadd45b from binding to its partner, MKK7. We have shown that these proteins don?t affect normal cells, making them promising starting points in the search for a new drug therapy. The next steps will be to find out how these molecules behave in models of cancer, and use this information to create a second generation of improved molecules. At the end of this study we aim to create a compound that can be given to patients within a year or two. This treatment will not only stabilise the disease, but may actually offer a cure for multiple myeloma. The team has wide experience of successful drug discovery and development within the pharmaceutical industry and will develop the peptide molecules using Imperial College?s extensive biological, chemical and clinical facilities.