Medicinal Chemistry Core

需要药物化学来支持转化癌症研究 在CCR中进行。开发新的小分子靶向临床重要 目标需要相当大的努力，在化学，以改善，优化，并了解 候选药物的活性。目前，在CCR的研究实验室和筛查中心， NCATS有相当多的筛选基础设施，可用于识别命中化合物， 微摩尔效力。然而，这样的命中物不具有合适的性质（例如效力、细胞毒性、免疫原性）。 渗透性，或ADME）用作选择性化学探针或被翻译成 诊所因此，项目往往会停滞，因为没有机制来推动这些分子超越 发现阶段。为了开发一种化合物，将命中物优化为先导物， 最终通过药物化学的努力成为临床候选人。一个成功的项目 可能需要100-1000种化合物的化学合成和评估，以产生 具有纳摩尔效力的化合物。将该电极导线开发为具有体内 活性和合适的ADME/Tox性质，然后再次需要第二轮优化 需要合成100-1000种以上的化合物和伴随的分析。一个或两 需要这些步骤来“降低”化合物的风险，使其对潜在的 许可或内部临床开发。这种类型的药物发现工作超出了 个体CCR研究者的资源、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.