Medicinal Chemistry Core

药物化学核心

• 批准号: 10703080
• 负责人: Joel Schneider
• 金额: $ 15.56万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703080
• 关键词: Biological Assay; CBL gene; CCR; Cells; Chemicals; Chemistry; Clinic; Clinical; Development; Evaluation; Goals; Individual; Infrastructure; Lead; Legal patent; Licensing; National Center for Advancing Translational Sciences; Permeability; Pharmaceutical Chemistry; Property; Research; Research Personnel; Resources; Risk; Translating; Work; chemical synthesis; clinical candidate; clinical development; drug candidate; drug discovery; improved; in vivo; lead series; nanomolar; preclinical development; screening; small molecule; structural biology; translational cancer research

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.

需要药物化学来支持CCR中正在进行的转化癌症研究。开发新的小分子以靶向临床重要的目标，需要在化学方面进行相当大的努力，以改善，优化和理解候选药物的活性。当前，在CCR和NCAT的研究实验室和筛选中心中，有相当大的筛选基础设施可用于鉴定具有微摩尔效力的命中化合物。但是，这种命中没有合适的特性（例如效力，细胞渗透性或ADME）作为选择性化学探针或将其转化为诊所。因此，项目通常停滞不前，因为没有机制可以将这些分子推向发现阶段。为了开发化合物，通过药物化学工作对铅和临床候选者进行了优化的命中率。命中率的项目可能需要化学合成和评估100-1000种化合物，以产生具有纳摩尔效力的化合物。这种发展导致具有体内活性和合适的ADME/TOX特性的临床候选者需要第二轮优化，再次需要合成100-1000种更多化合物和随附的测定。这些步骤中的一个或两个步骤都需要“降低风险”化合物，从而使其对潜在的许可或内部临床开发有吸引力。这种类型的药物发现工作超出了个别CCR研究人员的资源，专业知识和科学范围。