Self-Assembled Cryptate Kinase Inhibitors as Anti-Cancer Therapeutic Agents.

虽然在开发针对癌症生物学关键过程的新型抗癌药物方面取得了相当大的成就，但现实情况是，许多癌症仍然难以治疗。尽管靶向抗癌药物对癌症的治疗产生了重大影响，所有37种激酶抑制剂的临床有效性目前由FDA批准的抗肿瘤药物（抑制驱动癌细胞复制的重要酶的化合物）受到耐药性和毒性问题的严重影响。为了克服目前激酶抑制剂的局限性，我们开发并测试了有限数量的化合物，称为“三金属穴状配体”，由配体（L）和金属（M）组成，可以封装一系列阴离子（A）。通过将M、L和/或A以各种组合混合在一起，通过称为自组装的过程形成一系列穴状配体。自组装的穴状配体可以抑制多种激酶，并且与非癌细胞相比对癌细胞具有选择性毒性。靶向多种激酶同时保留对癌细胞的选择性的能力是一个重要的发现，因为（i）癌细胞将发现难以产生抗性，因为多个途径被“击中”，这与目前仅靶向一个或有限数量的途径的激酶抑制剂不同，以及（ii）选择性杀死癌细胞的能力表明存在“治疗窗口”，其中癌细胞被杀死而对正常组织的损害有限。由于我们只开发了有限数量的穴状配体，该项目的主要目标是制造更多的化合物，这些化合物可以被测试以识别对癌细胞有选择性毒性的新的“命中”。由于穴状配体由M、L和A组成，将每个组成部分的不同“风味”混合在一起，使得它们自组装以形成具有不同药理学性质的穴状配体，可以从相对少量的“成分”产生许多治疗活性药物。使用一个流行的比喻，一个特定的鸡尾酒是由几个组成部分，当混合在一起时，会产生一种独特的味道。配方可以变化，以产生一系列不同的鸡尾酒，每一种都有特定的味道。我们的方法使用了一系列不同的化学成分，当它们结合在一起时，可以产生一种“治疗鸡尾酒”，这种鸡尾酒具有特定的效果，每种鸡尾酒都有不同的效果。在未来，有可能通过这种方法用正确的药物“自组装”来靶向许多癌症，从而对癌症类型或个体患者的癌症具有选择性。通过探索“化学空间”和开发更多的化学“成分”，可以自组装形成具有不同特性的药物，我们有可能扩大我们可以开发的潜在药物的范围。了解这些化合物的化学性质及其在实验室中的活性是推动这项工作向前发展的重要一步，其目的是能够设计出“治疗鸡尾酒”，专门针对难以治疗的癌症，对癌细胞具有选择性活性，并且不会出现耐药性。最终目标是能够在患者床边组装药物，这些药物将靶向个体患者癌症中的关键生化特征，从而产生抗肿瘤活性并延长寿命。

Whilst there have been considerable achievements in the development of new cancer drugs that are 'targeted' at key processes involved in cancer biology, the reality is that many cancers remain hard to treat. Although targeted anti-cancer drugs have had a major impact on the treatment of cancers, the clinical effectiveness of all 37 kinase inhibitors (compounds that inhibit important enzymes that drive cancer cell replication) currently approved by the FDA is severely compromised by problems with drug resistance and toxicity. To override the current limitations of kinase inhibitors, we have developed and tested a limited number of compounds called 'trimetallic cryptands' composed of a ligand (L) and a metal (M) that can encapsulate a range of anions (A). By mixing M, L and/or A together in various combinations, a series of cryptands are formed by a process known as self-assembly. The self-assembled cryptands can inhibit multiple kinases and are selectively toxic to cancer cells compared to non-cancer cells. The ability to target multiple kinases whilst retaining selectivity for cancer cells is an important finding because (i) cancer cells will find it difficult to develop resistance as multiple pathways are being 'hit' which differs from current kinases inhibitors that target just one or a limited number of pathways and (ii) the ability to selectively kill cancer cells suggests that a 'therapeutic window' exists where cancer cells are killed with limited damage to normal tissues. As we have only developed a limited number of cryptands, the principle aim of this project is to make more compounds that can be tested to identify new 'hits' that are selectively toxic to cancer cells. As cryptands are made up of M, L and A, mixing different 'flavours' of each component part together so that they self-assemble to form cryptands with different pharmacological properties could generate many therapeutically active drugs from a relatively small number of 'ingredients'. To use a popular analogy, a specific cocktail is made up of several component parts which when blended together gives a characteristic taste. The recipe can be varied to produce a range of different cocktails, each of which has a specific flavour. Our approach uses a range of different chemical ingredients which when combined can give a 'therapeutic cocktail' that has a specific effect with each cocktail having different effects. In the future, it may be possible to target many cancers through this approach with the correct drug 'self-assembled' in such a manner as to be selective for a cancer type or an individual patient's cancer. By exploring the 'chemical space' and developing more chemical 'ingredients' that can be self-assembled to form drugs with different properties, we have the potential to expand the range of potential drugs that we have available to develop. Understanding the chemical properties of these compounds and their activity in the laboratory is an essential step that will drive this work forward where the aim is to be able to design 'therapeutic cocktails' that will specifically target hard to treat cancers, are selectively active to cancer cells and do not suffer from the emergence of drug resistance. The ultimate aim is to be able to assemble drugs at the patient's bedside that will target key biochemical features in that individual patient's cancer resulting in anti-tumour activity and prolonged life.