Targeting Causal Cancer Genes with Small Molecules

描述(申请人提供)：通过癌症基因组学和现代癌症生物学的进步，我们对癌症如何开始、存活和进展的理解正在迅速扩大。尽管这些见解建议了许多新的治疗干预策略，但它们往往需要调整靶点，而针对这些靶点，研究界几乎没有经验或成功地开发出小分子探针和药物。通过NCI分子靶标发现和发展中心网络试点计划，我们的目标是克服这一挑战，加快癌症新疗法的发现。 布罗德-MTDDC将向MTDDC网络提供在小分子探测器和药物开发方面的创新和执行方面超过10年的经验，以促进癌症生物界的见解。我们的目标是在基础化学方面进行创新，以便能够发现小分子探针，以针对甚至是那些从基因组研究中出现的“无法用药的”癌症靶标；让癌症生物界参与进来，并将小分子科学引入癌症的根本原因；以及解决靶标识别问题，包括通过全面确定癌症通路的小分子调节物与细胞内或细胞上的蛋白质结合的蛋白质。此外，我们将为癌症生物界提供所需的强大基础设施和专业知识，以执行旨在改变癌症疗法的探针和药物开发项目。 对人类健康的影响。布罗德研究所的分子靶标发现和开发中心将发现针对癌症根本原因和相关性的小分子。这些线索将成为新药开发计划的宝贵起点。通过提供早期的先导优化和来自临床相关动物模型的数据，我们的目标是推进癌症药物发现开发。此外，我们将公开所有与小分子探针开发相关的数据，使社区能够进一步发现药物，并就我们的药物发现方法进行更广泛的交流。 公共卫生相关性：布罗德研究所的分子靶标发现和开发中心将开发和执行癌症生物学社区的小分子筛查，旨在针对癌症的根本原因和相关性。我们将把重点放在化学、筛选和临床前研究方面的创新，以便使用现有的工具和方法获得被视为“不可用药”的靶点。这些项目将生产小分子探针，既可以使用动物模型对治疗策略进行临床前验证，又可以作为药物开发的杰出起点。

DESCRIPTION (provided by applicant): Our understanding of how cancers begin, survive and progress is rapidly expanding through advances in cancer genomics and modern cancer biology. Although these insights suggest many new strategies for therapeutic intervention, they often require modulating targets against which the research community has had little experience or success developing small-molecule probes and drugs. Through the NCI Molecular Target Discovery and Development Center Network Pilot Program, we aim to overcome this challenge and to accelerate the discovery of novel therapeutics in cancer. The Broad-MTDDC will provide over 10 years of experience in both innovation and execution in small- molecule probe and drug development to the MTDDC Network to advance insights from the cancer biology community. We aim to innovate in fundamental chemistry so as to enable the discovery of small-molecule probes against even 'undruggable' cancer targets such as those emerging from genomic studies; to engage the cancer biology community and to bring small-molecule science to the root causes of cancer; and to solve the target I.D. problem, including by determining comprehensively the proteins to which small-molecule modulators of cancer pathways bind in or on cells. Furthermore, we will provide the cancer biology community with the robust infrastructure and expertise required to execute probe- and drug-development projects that aim to transform cancer therapeutics. Impact on human health. The Molecular Target Discovery and Development Center at the Broad Institute will discover small molecules that target the root causes and dependencies of cancer. These leads will serve as valuable starting points for new drug development programs. By providing early lead optimization and data from clinically relevant animal models, we aim to advance cancer drug discovery development. Furthermore, we will make all data associated with small-molecule probe development publicly available, enabling further discovery from the community and broader communication of our approaches to drug discovery. PUBLIC HEALTH RELEVANCE: The Molecular Target Discovery and Development Center at the Broad Institute will develop and execute small-molecule screens from the cancer biology community aimed at targeting the root causes and dependencies of cancer. We will focus on innovation in chemistry, screening, and preclinical research in order to access targets viewed as 'undruggable' using current tools and approaches. These projects will yield small- molecule probes that both enable pre-clinical validation of therapeutic strategies using animal models and serve as outstanding starting points for drug development.