Addressing Undruggable Targets Using Oligonucleotides and Small Molecules (PQ18)

描述（由申请人提供）：作为对PQ18的回应，我们建议通过创新的寡核苷酸和小有机分子的联合使用，通过传统手段解决“不可药物”的癌症相关靶点。目前，人们对反义和siRNA寡核苷酸在癌症和其他疾病中的治疗潜力产生了极大的兴趣，多项临床试验正在进行中。然而，无法有效地将这些高极性分子运送到组织内的细胞内作用位点仍然是一个主要障碍

DESCRIPTION (provided by applicant): In response to PQ18 we propose to address cancer-related targets that are 'undruggable' by conventional means through an innovative conjoint use of oligonucleotides and small organic molecules. There is currently tremendous interest in the therapeutic potential of antisense and siRNA oligonucleotides in cancer and other diseases, with multiple clinical trials underway. However, the inability to effectively deliver these highly polar molecules to their intracellular sites of action within tissues remains a major impediment to progress. In this PQ application we describe a novel chemical biology strategy for oligonucleotide delivery, one that is radically different from the approaches now in common use. Recent studies from our laboratory and others have shown that the pathway of cellular uptake and intracellular trafficking followed by an oligonucleotide can have a major impact on its pharmacological actions. Here we propose to manipulate oligonucleotide trafficking pathways and subsequent pharmacological effects using small organic molecules that we term OTECs ('oligonucleotide trafficking enhancer compounds'). We have already established a proof of principle for this approach using a set of small molecules that affect early endosome to trans-Golgi traffic. These agents provide a marked enhancement of oligonucleotide action in cell culture studies when used at micromolar concentrations. In the context of PQ18 we now propose to: (i) use OTECs and oligonucleotides to manipulate the functions of a transcription factor important in cancer; (ii) test whether OTEC compounds can act in xenograft tumors; (iii) use high throughput screening (HTS) to seek new, more potent OTEC-type compounds that work in the nanomolar range to enhance oligonucleotide action. Successful completion of these aims would have a transformative effect on the prospects for using oligonucleotides in cancer therapy, including the ability to address 'undruggable' targets.