Synthetic Spliceosome Probes and Modulators

描述（由申请人提供）：剪接体是癌症治疗的重要新兴靶点，其仅在最近才被发现并且仍有待于显著开发。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，以允许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，发现两种不相关的天然产物FR 901464（FR）和普拉地那肽（PD）均通过抑制剪接体的SF 3b亚基而起作用。这两种天然产物在体内抗肿瘤模型中均显示出活性。特别地，普拉地那肽和类似物已经显示出惊人的体内抗肿瘤选择性和功效，具有显著的治疗窗口。事实上，普拉地那肽B的衍生物（E7107）已进入I期人体临床试验。这些天然产物和衍生自它们的类似物是相当复杂的，并且它们的类似物的合成是相当苛刻的。可以容易地得出结论，发现通过调节剪接体起作用的活性简化化合物的更容易的途径是整个药物发现界的重要目标。我们最近报道了FR的新型高度稳定的合成类似物的简明合成，其对多种易感肿瘤系的体外细胞毒性IC 50值低至40-80 nM，并且在小鼠肿瘤模型中具有有希望的体内活性（参见初步结果部分）。该提案的总体长期目标是更好地理解剪接体功能，开发用于治疗最易受剪接体调节的人类癌症的新药，并阐明剪接体调节剂的选择性作用机制。我们建议开发工具和优化的先导化合物，能够在体内有效的剪接体调制。我们计划通过探索我们目前的活性化合物对肿瘤中选择性剪接的影响，并通过多次迭代合成和精心设计的新类似物的体外测试来完善我们的剪接体调节剂，然后进行几个实验周期，包括详细研究我们的先导化合物的药理学，来实现这一目标。

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.