The Development of Inhibitors of Cdk Activating Kinase (CAK)

乳腺癌是西方女性最常见的癌症，80%的乳腺癌含有雌激素受体。他莫昔芬是内分泌敏感性乳腺癌的标准治疗药物。然而，虽然28%的患者在接受原发性乳腺癌手术的辅助治疗后，通常会出现耐药细胞，尽管这些新出现的乳腺癌细胞通常位于转移部位，仍然含有雌激素受体，这是药物的靶点。国家癌症研究所（美国）估计，2007年美国将有18万多例新的乳腺癌确诊病例，其中4万多例死亡。英国的可比数据分别为4.4万和1.25万。2007年，全球7大医药市场新诊断的乳腺癌患者总数预计将超过45万。乳腺癌是35-54岁年轻妇女死亡的最常见原因，占所有死亡人数的17%。乳腺癌的高发病率和随之而来的发病率和死亡率是确定新的药物治疗方案的主要驱动因素。临床迫切需要发现新的和改良的治疗癌症的药物。新药和显像剂的发现是一项多学科的努力。它涉及临床医生谁确定需要新的治疗方法来控制和治愈疾病。新药的发现涉及许多其他科学家，包括药理学家、分子生物学家和化学家。化学在所有药物的发现、开发和生产中起着绝对重要的作用。毫无例外，所有药物都是化学物质，绝大多数是分子量低于600的有机化合物。一种新药的发现需要化学家合成新的化合物，这样它们的生物效应就可以被测试、优化，并最终被医院的临床医生使用。一旦确定了一种活性原型药物，化学家就准备额外的新化合物进行分析。如果研究成功，而药物发现非常困难，那么这种化合物将被用于治疗乳腺癌等疾病。该提案的重点是伦敦帝国理工学院癌症医学临床小组和同一所大学合成化学小组之间的合作研究项目，重点是发现新药。在迄今为止的研究中，他们已经确定了一系列新的抑制剂，这些抑制剂非常有希望开发一种新的药物来治疗耐药乳腺癌患者。这项后续提案将允许伦敦团队与他们在埃默里大学的美国合作者一起充分开发这些新药以实现商业化。

Breast cancer is the most common form of cancer in women in the western world, and 80% of breast cancers contain estrogen receptor. Tamoxifen is the standard treatment for endocrine sensitive breast cancer. However, whilst curing 28% of people who are given it as an adjuvant to surgery for primary breast cancer, it is commonly followed by the emergence of resistant cells despite the fact that these emerging breast cancer cells, which are often in metastatic sites still containing estrogen receptor, the very target of the drug. The National Cancer Institute (USA) estimate that in the USA in 2007 there will be over 180,000 new cases of breast cancer diagnosed with over 40,000 deaths. The comparable figures for the UK are 44,000 and 12,500 respectively. In 2007, the total numbers of newly diagnosed breast cancer patients in the 7 top pharmaceutical markets in the world are expected to exceed 450,000. Breast cancer is the most common cause of all deaths in younger women aged 35-54 years, accounting for 17% of all deaths. The high incidence of breast cancers and the attendant morbidity and mortality are major drivers for the identification of novel drug treatment regimes. There is an urgent clinical need for the discovery of new and improved drugs to treat cancer. The discovery of new medicines and imaging agents is a multidisciplinary endeavour. It involves clinicians who identify a need for new therapies to control and cure disease. The discovery of new medicines involves many other scientists including pharmacologists, molecular biologists and chemists. Chemistry plays an absolutely vital role in the discovery, development and manufacture of all medicines. Without exception, all medicines are chemicals and the vast majority are organic compounds with molecular weights below 600. The discovery of a new medicine requires the chemist to synthesise new compounds so that their biological effects can be tested, optimised and ultimately used by clinicians in a hospital setting. Once an active prototype drug has been identified, the chemist prepares additional new compounds for assay. If the research is successful, and pharmaceutical discovery is very difficult, then the compound will be used to cure diseases such as breast cancer. This proposal is focused on a collaborative programme of research between a clinical group in Cancer Medicine at Imperial College London and a group in Synthetic Chemistry in the same university with focus on the discovery of new medicines. In research to date they have identified a novel series of inhibitors that are highly promising for the development of a new class of drugs to treat patients with resistant breast cancers. This follow on proposal will allow the London team, along with their American collaborators in Emory University, to fully develop these new drugs for commercialisation.