Synthetic Slicesome Probes and Modulators

合成切片体探针和调制器

• 批准号: 8787673
• 负责人: Thomas Roy Webb
• 金额: $ 22.04万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787673
• 关键词: Synthetic; Slicesome; Probes; Modulators

DESCRIPTION (provided by applicant): The spliceosome is an important emerging target for cancer therapy that has only recently been uncovered and remains to be significantly exploited. The development of highly selective anti-tumor agents continues to be a challenge in drug discovery and this fact has motivated researchers to search for new molecular targets that allow for the discovery of more selective anticancer agents than has been possible with compounds that inhibit many of the classic cancer targets. Recently, it was discovered that two unrelated natural products FR901464 (FR) and pladienolide (PD) both act by inhibition of the SF3b subunit of the spliceosome. Both of these natural products show activity in in vivo anti-tumor models. In particular, pladienolide and analogs have shown striking in vivo anti-tumor selectivity and efficacy, with a pronounced therapeutic window. In fact, a derivative of pladienolide B (E7107) has been advanced to Phase I human clinical trials. These natural products, and analogs derived from them, are quite complex and the synthesis of their analogs is quite demanding. It can readily be concluded that the discovery of more facile routes to active simplified compounds that work by modulation of the spliceosome is an important goal for the drug discovery community at large. We have recently reported the concise synthesis of novel highly stabilized synthetic analogs of FR that possess in vitro cytotoxicity IC50 values as low as 40-80 nM against multiple susceptible tumor lines and promising in vivo activity in a mouse tumor model (see Preliminary Results section). The overall long-term goal of this proposal is the development of a better understanding of spliceosome function, the development of new drugs for the treatment of human cancers that are most vulnerable to spliceosome modulation and elucidation of the mechanism of selective action of spliceosome modulators. We propose to develop both tool and optimized lead compounds capable of potent spliceosome modulation in vivo. We plan to accomplish this through exploration of the effects of our current active compounds on alternate splicing in tumors and through the refinement of our spliceosome modulators via multiple iterations of synthesis and in vitro testing of carefully designed new analogs, followed by several experimental cycles involving detailed investigations of the pharmacology of our lead compounds.

描述（由申请人提供）：剪接体是一种重要的新兴癌症治疗靶点，最近才被发现，仍有待开发。高选择性抗肿瘤药物的开发仍然是药物发现中的一个挑战，这一事实促使研究人员寻找新的分子靶点，从而发现比抑制许多经典癌症靶点的化合物更有选择性的抗癌药物。最近，人们发现两种不相关的天然产物FR901464 （FR）和pladienolide （PD）都通过抑制剪接体的SF3b亚基起作用。这两种天然产物在体内抗肿瘤模型中都显示出活性。特别是，铂烯内酯和类似物已经显示出惊人的体内抗肿瘤选择性和有效性，具有明显的治疗窗口。事实上，pladienolide B （E7107）的衍生物已经进入I期人体临床试验。这些天然产物及其衍生的类似物非常复杂，其类似物的合成要求很高。可以很容易地得出结论，通过调节剪接体来发现更容易的活性简化化合物的途径是药物发现界的一个重要目标。我们最近报道了一种新的高度稳定的FR合成类似物的简明合成，其体外细胞毒性IC50值低至40-80 nM，对多种易感肿瘤系具有抑制作用，并且在小鼠肿瘤模型中具有良好的体内活性（见初步结果部分）。本研究的长期目标是更好地理解剪接体的功能，开发新的药物来治疗最易受剪接体调节的人类癌症，并阐明剪接体调节剂的选择作用机制。我们建议开发工具和优化的先导化合物能够在体内有效地调节剪接体。我们计划通过探索我们目前的活性化合物对肿瘤中交替剪接的影响，以及通过多次合成迭代和精心设计的新类似物的体外测试来改进我们的剪接体调节剂，然后进行几个实验周期，包括对我们的先导化合物的药理学的详细研究，来实现这一目标。