Splicing Modulators for Rare Disease Indications

几年前，我们确定了聚酮化合物GEX1a(Herboxdiene)和二烯内酯是潜在的 用于两种适应症的先导化合物，这两种适应症没有提及，但目前正在进行化疗治疗。 Niemann-Pick C型是一种罕见的致命性遗传病，与异常的胆固醇和 溶酶体内的鞘磷脂储存，目前没有FDA批准的治疗方法，最近 候选人在后期试验中的结果令人失望。在我们国家卫生研究院的最新研究期间 R01授权，我们用新的结果补充了这一发现，表明GEX1A具有强大的选择性 FMS样酪氨酸激酶3(Flt3)基因突变的抗急性髓系白血病活性 吉恩。Flt3突变是急性髓系白血病最常见的体细胞突变 (AML)和它们的存在可能是预后不良的一个因素，并仍然是一个临床挑战 需要新的治疗方案。虽然最初研究的是它们的抗癌潜力，但初步的 这些多酮的结果指向与调节相关的和/或额外的活性 突变型NPC1蛋白等基因产物通过前RNA剪接调控。最近的FDA- 目前临床上批准的药物和候选药物表明，RNA剪接的调节和 剪接体是越来越具有临床意义的生物学靶点。在这两个迹象中，我们都有 通过体外细胞研究和体内小鼠模型显示了活性。因此，具有治疗作用 已经确定的剂量没有潜在的毒性，因此我们的持续努力被视为既 在基础研究和翻译研究方面具有重大意义和创新性。协作性、 多学科策略利用细菌发酵、天然产物降解和半合成 作为对全合成的补充，为生物研究提供化合物的途径 药理优化。我们将确定GEX1A和GEX1A的解决方案构象偏好 并将此信息应用于构象类似物的设计和合成 全化学合成。合成技术的结合将确保充足的天然气供应 GEX1A和相关类似物，用于一些关键的生化实验，以帮助建立和 将这两种适应症的作用机制联系起来。最后，我们将继续努力评估 通过小鼠体内活性研究优化同源基因的翻译潜力 鼻咽癌疾病模型。将对两个小鼠、整个动物模型进行评估。更好地理解 这种作用模式可以帮助识别Niemann-Pick C型和其他溶酶体之间的共同点 疾病，以及更常见的疾病。大约2500万美国人受到一种罕见疾病的影响 疾病研究有可能增加我们对更常见疾病的了解 他们的书房。

Several years ago we identified polyketides GEX1A (herboxidiene) and the pladienolides as potential lead compounds for two indications that are not addressed but current chemotherapeutic treatments. Niemann-Pick Type C is a rare, lethal genetic disease associated with aberrant cholesterol and sphingolipid storage within the lysosome with no current FDA-approved treatment and recent disappointing results of candidates in late-stage trials. During the most recent research period of our NIH R01 grant, we complemented this discovery with new results that show GEX1A has potent and selective activity against acute myeloid leukemia with mutations within the FMS-like tyrosine kinase 3 (FLT3) gene. FLT3 mutations are the most common somatic mutations observed in acute myeloid leukemia (AML) and their presence may be a prognostic factor for poor outcome and remain a clinical challenge in need of new treatment options. Although originally investigated for their anti-cancer potential, preliminary results with these polyketides point to related and/or additional activity associated with modulation of mutant NPC1 protein and other gene products through pre-RNA splicing modulation. Recent FDA- approved drugs and candidates in current clinic suggests that modulation of RNA-splicing and the spliceosome are biological targets with growing clinical relevance. In both indications we have demonstrated activity through in vitro cellular studies and in vivo mouse models. Thus, therapeutic dosages have been identified without potential toxicity and thus our continued effort is seen as both significant and innovative with respect to fundamental and translational research. The collaborative, multidisciplinary strategy utilizes bacterial fermentation, natural product degradation and semi-synthesis as a complement to total synthesis as means to provide access to compounds for biological studies and pharmacological optimization. We will determine the solution conformational preferences of GEX1A and pladienolides and apply this information to the design and synthesis of conformational analogues through total chemical synthesis. The combination of synthetic technologies will ensure an adequate supply of GEX1A and related analogues for a number of key biochemical experiments to help establish and correlate the mechanisms of action in both indications. Finally, we will continue our efforts to evaluate the translational potential of optimized congeners through exploration of their in vivo activity in mouse models of NPC disease. Two murine, whole animal models will be assessed. A greater understanding of the mode of action can help identify commonalities between Niemann-Pick Type C, other lysosomal disorders, and more common diseases. About 25M Americans are affected by a rare disease and rare disease research has the potential to increase our understanding of more common afflictions through their study.