Bcl-2 selective inhibitors: development and application to cancer treatment

Bcl-2选择性抑制剂：开发及其在癌症治疗中的应用

• 批准号: 7145178
• 负责人: CHENGGUO XING
• 金额: $ 20.82万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145178
• 关键词: drug resistance; neoplasm /cancer; proteins

DESCRIPTION (provided by applicant): Drug resistance is a significant stumbling block in the fight against cancer. Small molecules that inhibit anti- apoptotic Bcl-2 proteins have the potential to overcome such drug resistance. Most of current small- molecule inhibitors non-selectively target multiple anti-apoptotic Bcl-2 proteins. It remains to be determined: 1) whether a selective inhibitor will be effective in overcoming drug resistance; 2) whether non-selectively inhibiting multiple anti-apoptotic Bcl-2 proteins may introduce more toxicity against healthy tissues; 3) whether non-selectively inhibiting multiple anti-apoptotic Bcl-2 proteins may be less effective in the treatment of certain cancers since it is questionable that all endogenous anti-apoptotic Bcl-2 proteins have protective functions in all tumors. Our long-term goal is to develop chemical probes for anti-apoptotic Bcl-2 proteins to help study their functions in various tumors and to develop small-molecule inhibitors for cancer treatment. Our central hypothesis for this proposed research is that member-selective inhibitors of anti-apoptotic Bcl-2 proteins will selectively induce / sensitize the cancers that overexpress such a protein to apoptosis. This central hypothesis is formulated based on the following observations. First, though some tumors simultaneously overexpress multiple anti-apoptotic Bcl-2 proteins, many tumors only overexpress a single anti-apoptotic Bcl- 2 protein. The selective overexpression of one anti-apoptotic Bcl-2 protein suggests that a selective inhibitor would be effective in overcoming the drug resistance. Second, a Bcl-2 inhibitor identified by Wang et al (YC 137) selectively induces apoptosis in a tumor cell line that overexpresses Bcl-2 protein and shows less toxicity to normal cells. Third, a Bcl-2 selective inhibitor identified in our laboratory can effectively overcome the drug resistance induced by Bcl-2 overexpression (Preliminary Studies). Based on these observations, the focus of this proposal is on the development of selective inhibitors for anti-apoptotic Bcl-2 proteins and their evaluation against primary tumors for cancer treatment. The specific aims are to: 1. Identify a set of inhibitors for Bcl-2, Bcl-XL, and Bcl-w with stringent selectivity (two for each protein). We will 1) rationally design and synthesize a 72-member library based on a promising template by using molecular modeling and solid-phase synthesis; 2) identify the selective inhibitors by a solid-phase assay; and 3) determine their absolute binding selectivity. 2. Examine the effect of binding selectivity on the potential for selective toxicity to tumors over healthy tissues and the potential of sensitizing tumors to conventional cancer treatment. We will 1) evaluate our current selective and non-selective inhibitors for their cytotoxicity against hematologic primary tumors and healthy blood cells; 2) evaluate our current selective inhibitors for their potential synergism with clinical therapies against the hematologic primary tumors.

描述（由申请人提供）：耐药性是打击癌症的重要绊脚石。抑制抗凋亡Bcl-2蛋白的小分子具有克服这种耐药性的潜力。当前的大多数小分子抑制剂非选择性靶向多个抗凋亡Bcl-2蛋白。尚待确定：1）选择性抑制剂是否有效克服耐药性； 2）非选择性抑制多种抗凋亡的Bcl-2蛋白是否会引入对健康组织的更多毒性； 3）非选择性抑制多种抗凋亡的Bcl-2蛋白是否在治疗某些癌症方面的有效性较低，因为所有内源性抗凋亡BCL-2蛋白在所有肿瘤中均具有保护功能是值得怀疑的。我们的长期目标是开发抗凋亡Bcl-2蛋白的化学探针，以帮助研究其在各种肿瘤中的功能，并开发用于癌症治疗的小分子抑制剂。我们对这项拟议的研究的中心假设是，抗凋亡Bcl-2蛋白的成员选择性抑制剂将有选择地诱导 /敏化过表达这种蛋白质的癌症。该中心假设是根据以下观察结果提出的。首先，尽管某些肿瘤同时表达了多种抗凋亡BCL-2蛋白，但许多肿瘤仅表达单个抗凋亡BCl-2蛋白。一种抗凋亡Bcl-2蛋白的选择性过表达表明，选择性抑制剂将有效克服耐药性。其次，Wang等人（YC 137）鉴定出的Bcl-2抑制剂在肿瘤细胞系中有选择地诱导过表达Bcl-2蛋白的凋亡，并且对正常细胞的毒性较小。第三，在我们的实验室中鉴定出的BCL-2选择性抑制剂可以有效克服Bcl-2过表达引起的耐药性（初步研究）。基于这些观察结果，该提案的重点是抗凋亡Bcl-2蛋白的选择性抑制剂的开发及其针对癌症治疗的原发性肿瘤的评估。具体目的是：1。确定一组Bcl-2，Bcl-XL和Bcl-W具有严格的选择性（每种蛋白质的抑制剂）。我们将通过使用分子建模和固相合成，基于有希望的模板合理设计并合理设计并合成一个72成员的库； 2）通过固相测定确定选择性抑制剂； 3）确定它们的绝对结合选择性。 2。检查结合选择性对健康组织肿瘤选择性毒性的潜力的影响，以及使肿瘤对常规癌症治疗的潜力。我们将1）评估我们当前的选择性和非选择性抑制剂，以针对血液学原发性肿瘤和健康血细胞的细胞毒性； 2）评估我们当前的选择性抑制剂，以通过针对血液学原发性肿瘤进行临床疗法的潜在协同作用。