SCREENING TECHNOLOGY FOR CANCER THERAPEUTICS

长期以来，人们一直认为癌细胞已经失去了正常的细胞 增长控制。最近的研究已经证明了一种相关性 在细胞周期调节的特定缺陷和各种 癌症。在SBIR拨款的第一阶段，BitTech，Inc.开发了 细胞周期蛋白/细胞周期蛋白依赖性激酶的体内表型筛选 (细胞周期蛋白/CDK)功能。细胞周期蛋白/CDK是细胞周期蛋白的关键调节因子 真核细胞周期调控，并放置了三个报告基因 在启动子的控制下，该启动子由特定的 细胞周期蛋白/CDK。第一阶段的研究进一步证明了 使用BitTech的核心技术来测量对周期药物的影响， CDK或CDK抑制蛋白(CKI)。在第二阶段，核心 将进一步开发用于靶向筛查的技术 程序。在人类细胞周期中产生的细胞系 已知的突变或异常的调节蛋白 在特定的癌症中被调节，被合并为分子靶标 在表型屏幕上。这些高吞吐量的测试材料 筛选可以表达来自各种细胞类型的cdna，存在 化学库、新的组合库或Rational的产品 设计程序。因为这些化合物将在 对突变型或突变型蛋白质具有高度特异性的筛选 在癌细胞中异常调节，它们(或类似物从 先导化合物)有望表现出更好的功效和 与目前可用的相比，患者的副作用减少 治疗。 建议的商业应用 目前的癌症治疗方法往往是无效的，而且有显著的 对病人的副作用。细胞周期蛋白/CDK的体内筛选 功能针对的是关键的细胞周期调节蛋白，这些蛋白是 某些癌症有缺陷的。因此，治疗性化合物 用这项技术发现的人有望表现出更好的 有效率，减少了患者的副作用。这样的疗法将会 降低癌症相关发病率和医疗成本。

It has long been understood that cancer cells have lost normal cellular growth control. Recent research has demonstrated a correlation between specific defects in cell cycle regulation and a variety of cancers. During Phase I of this SBIR grant, BitTech, Inc. developed in vivo phenotypic screens for cyclin/cyclin dependent kinase (cyclin/CDK) function. Cyclin/CDKs are the key regulators of eukaryotic cell cycle control, and three reporter genes were placed under control of a promoter which is regulated by a specific cyclin/CDK. Phase I research further demonstrated the feasibility of using the BitTech core technology for measuring effects on cyclins, CDKs or CDK inhibitor proteins (CKIs). During Phase II, the core technology will be further developed for use in targeted screening programs. Cell lines will be generated in which human cell cycle regulatory proteins, which are known to be mutant or aberrantly regulated in specific cancers, are incorporated as the molecular targets in the phenotypic screens. The test material for these high throughput screens may be expressed cDNA from various cell types, existing chemical libraries, new combinatorial libraries or products of rational design programs. Because these compounds will be discovered in screens which are highly specific for proteins which are mutant or aberrantly regulated in cancer cells, they (or analogues developed from the lead compound) are expected to exhibit improved efficacy and reduced side effects for the patients, compared to currently available therapies. PROPOSED COMMERCIAL APPLICATION Current cancer therapies are frequently ineffective and have significant side effects for the patient. The in vivo screens for cyclin/CDK function are targeted to the key cell cycle regulatory proteins which are defective in certain cancers. Therefore, therapeutic compounds discovered with this technology are expected to exhibit improved efficiency and reduced side effects for the patient. Such therapies will decrease cancer-associated morbidity and health care costs.