Chemistry and Cancer Scientific Program

哈罗德·西蒙斯癌症中心 化学与癌症科学计划 项目摘要/摘要 化学与癌症(CC)计划结合了合成化学家和药物化学家的专业知识， 分子生物学家、生物化学家、结构生物学家和临床科学家来发现、设计和优化 类药物小分子，调节在癌症中放松调控的生物途径。一共有16个 来自校园内4个部门的成员。CC的发现过程双管齐下 方法，从化学到生物或从生物到化学的方向。从化学到生物 方法，发现过程开始于识别有选择性的天然或非天然小分子 对人类癌细胞系具有细胞毒性，随后进行严格的靶标识别程序。在这个“发现”过程中 在“生物学”阶段，化学家设计了特定的衍生品，以帮助进行生化下拉和交联性研究。 或者，如果可以产生针对目标小分子的特定抗药性克隆，遗传和 分子生物学研究可以提供更多的方法来识别靶途径和/或药物 抗性机制。这种不偏不倚的方法有望识别新的癌症特异性途径， 可以对其进行化学讯问/管制，以进行概念验证和早期药物发现工作。在生物学上-到- 化学方法，关于特定生物的“可药性”和癌症相关性的假设 西蒙斯癌症中心科学家研究的通路可以用小分子激动剂或 对抗者。 CC科学计划将继续广泛开展以下主题： ·主题1.确定癌细胞特异性小分子毒素的分子靶标； ·主题2.对新的癌细胞特有途径的生化剖析； ·主题3.针对癌细胞的小分子毒素的概念验证临床前开发；以及 ·主题4.低氧反应途径的解剖、调节和靶向。 目前经同行审查的CC计划资金主要来自NCI的150万美元和280万美元 来自德克萨斯州癌症预防和研究所的同行评审资金总额为710万美元。抄送 自2009年以来，计划成员已经撰写了103份同行评议的出版物，其中19%是内部审查的- 方案和30%的方案间，其中15%是机构间的，有来自其他机构的调查人员 NCI指定的癌症中心。

Harold C. Simmons Cancer Center Chemistry and Cancer Scientific Program Project Summary/Abstract The Chemistry and Cancer (CC) Program combines the expertise of synthetic and medicinal chemists, molecular biologists, biochemists, structural biologists, and clinician scientists to discover, design, and optimize drug-like small molecules that regulate biological pathways deregulated in cancer. There are a total of 16 members who are drawn from 4 departments on campus. CC's discovery process takes a two-pronged approach, starting from a chemistry-to-biology or a biology-to-chemistry direction. For the chemistry-to-biology approach, the discovery process starts with identifying natural or unnatural small molecules that are selectively cytotoxic to human cancer cell lines, followed by a rigorous target identification program. During this “discovery biology” phase, chemists design specific derivatives to aid in biochemical pull-down and cross-linking studies. Or, if specific drug-resistant clones against the small molecule of interest can be generated, genetic and molecular biological studies can provide additional approaches to identify target pathways and/or drug resistance mechanisms. This unbiased approach is expected to identify novel cancer-specific pathways that can be chemically interrogated/regulated for proof-of-concept, early drug-discovery efforts. In the biology-to- chemistry approach, hypotheses regarding the “drugability” and cancer relevance of specific biological pathways investigated by Simmons Cancer Center scientists can be tested with small-molecule agonists or antagonists. The CC Scientific Program will continue broadly with the following themes: · Theme 1. Identifying the molecular targets of cancer cell–specific small-molecule toxins; · Theme 2. Biochemical dissection of novel, cancer cell–specific pathways; · Theme 3. Proof-of-concept preclinical development of cancer cell–specific small-molecule toxins; and · Theme 4. Dissection, regulation, and targeting of the hypoxia response pathway. Current peer-reviewed funding for the CC Program is highlighted by $1.5 million from the NCI and $2.8 million from Cancer Prevention and Research Institute of Texas for total peer-reviewed funding of $7.1 million. CC Program members have authored 103 peer-reviewed publications since 2009, of which 19% were intra- programmatic and 30% inter-programmatic, and 15% of them inter-institutional with investigators from other NCI-designated cancer centers.