Medicinal Chemistry Core

需要药物化学来支持CCR内正在进行的转译癌症研究。开发以临床重要靶点为靶点的新小分子需要在化学上付出相当大的努力来改进、优化和了解候选药物的活性。目前，在CCR和NCATS的研究实验室和筛选中心内，有相当多的筛选基础设施可用于识别具有微摩尔效力的命中化合物。然而，这种HITS没有合适的性质(如效价、细胞渗透性或ADME)来用作选择性化学探针或转移到临床上。因此，项目经常停滞不前，因为没有机制将这些分子推进到发现阶段之后。为了开发一种化合物，HITS被优化为先导，并最终通过药物化学努力成为临床候选药物。一个Hit-to-Lead项目可能需要对100-1000种化合物进行化学合成和评估，以产生具有纳摩尔效力的化合物。要开发出具有体内活性和合适的ADME/Tox特性的临床候选药物，则需要进行第二轮优化，再次需要合成100-1000个以上的化合物和相应的检测方法。这两个步骤中的一个或两个都是为了降低化合物的风险，使其对潜在的许可或内部临床开发具有吸引力。这种类型的药物发现工作超出了CCR调查人员的资源、专业知识和科学范围。

There is a need for medicinal chemistry to support translational cancer research ongoing within CCR. The development of new small molecules to target clinically important targets requires considerable effort in chemistry to improve, optimize, and understand the activity of drug candidates. Currently, within research labs and screening centers in CCR and NCATS there is considerable screening infrastructure available to identify hit compounds with micromolar potency. However, such hits do not have suitable properties (such as potency, cell permeability, or ADME) to be used as selective chemical probes or to be translated to the clinic. Thus, projects often stall as there is no mechanism to advance these molecules beyond the discovery stage. In order to develop a compound, hits are optimized to leads and eventually clinical candidates through medicinal chemistry efforts. A hit-to-lead project might require the chemical synthesis and evaluation of 100-1000 compounds to generate a compound with nanomolar potency. Development of this lead to a clinical candidate with in vivo activity and suitable ADME/Tox properties then requires a second round of optimization, again requiring the synthesis of 100-1000 more compounds and the accompanying assays. One or both of these steps is required to "de-risk" a compound, making it attractive for potential licensing or internal clinical development. This type of drug discovery work is beyond the resources, expertise, and scientific scope of individual CCR investigators.