Optimization of compounds that selectively inhibit protein synthesis for the trea

描述（由申请人提供）：该项目的目标是开发并最终商业化抑制帽依赖性翻译起始的小分子药物，用于治疗三阴性（雌激素受体、孕激素受体和HER2阴性）乳腺肿瘤，重点是减少复发和提高生存率。与其他形式的乳腺癌不同，三阴性肿瘤没有靶向治疗方法。不幸的是，三阴性乳腺癌的侵袭性特别强，比其他乳腺癌亚型更容易复发，导致死亡风险增加。高比例的三阴性乳腺肿瘤具有高水平的eIF4E表达，并且eIF4E水平升高已被证明与较高的复发率和死亡风险增加相关。因为高水平的eIF4E代表着高的帽依赖翻译率；本提案的重点是选择性地抑制蛋白质的帽依赖翻译的化合物。因此，在乳腺癌模型中测试了先前确定的选择性抑制帽依赖性翻译的小分子，并选择了先导化合物进行进一步开发。在第一阶段，将合成更多的化合物，并评估选择性帽依赖翻译与抑制癌细胞生长之间的相关性，并建立癌症生长抑制的结构活性关系。这些化合物将在原代成纤维细胞、外周血单核细胞和CD34+细胞上进行测试，以确定对正常细胞的毒性。化合物也将在基于细胞的检测中测试帽依赖翻译的产物，以帮助阐明作用机制。上述测定中的化合物合成和表征将以迭代的方式进行，直到确定候选先导物。铅分子将至少具有微摩尔活性，对非恶性细胞的毒性最小，并且稳定，适合药物开发，并且新颖。先导化合物将按比例放大并进一步表征药代动力学和安全性。体内疗效和其他支持ind的临床前研究将在II期进行。由此产生的候选药物将为三阴性乳腺癌提供首个靶向小分子治疗。该项目的具体目标是：1)通过100-150个额外化合物的合成和生物学测试来开发先导化合物的SAR， 2)评估体外PK特性，3)扩大规模并表征先导化合物，4)确定体内PK和安全性。

DESCRIPTION (provided by applicant): The goal of this program is to develop and ultimately commercialize small molecule drugs that inhibit cap- dependent translation initiation for the treatment of triple negative (estrogen receptor, progesterone receptor, and HER2 negative) breast tumors with an emphasis on reducing recurrence and increasing survival rates. Unlike other forms of breast cancer, no targeted therapy exists for triple negative tumors. Unfortunately, triple negative breast cancers can be particularly aggressive and more likely to recur than other breast cancer subtypes, resulting in an increased risk of death. A high percentage of triple negative breast tumors have high levels of eIF4E expression and elevated levels of eIF4E have been shown to correlate with higher rates of recurrence and increased risk of death. Because high levels of eIF4E represent high rates of cap-dependent translation; the focus of this proposal is on compounds that selectively inhibit cap-dependent translation of proteins. Therefore, previously identified small molecules that selectively inhibit cap-dependent translation were tested in breast cancer models and lead compounds were selected for further development. In phase I, additional compounds will be synthesized and the correlation between selective cap-dependent translation and inhibition of cancer cell growth evaluated and structure activity relationships developed for cancer growth inhibition. These compounds will be tested on primary fibroblasts, peripheral blood mononuclear cells, and CD34+ cells to determine toxicity to normal cells. Compounds will also be tested in cell based assays for products of cap-dependent translation to help elucidate mechanism of action. Compound synthesis and characterization in the above assays will be performed in an iterative manner until lead candidates are identified. Lead molecules will have at least micromolar activity, minimal toxicity to non-malignant cells, and be stable, amenable to drug development, and novel. Lead compounds will be scaled up and further characterized for pharmacokinetic and safety properties. In vivo efficacy and other IND-enabling pre-clinical studies will be performed in phase II. Resulting drug candidates will provide the first targeted small molecule therapy for triple negative breast cancer. The specific aims for this project are: 1) develop SAR of lead compounds through synthesis and biological testing of 100-150 additional compounds, 2) assess in vitro PK properties, 3) scale up and characterize lead compounds, and 4) determine in vivo PK and safety. PUBLIC HEALTH RELEVANCE: The goal of this program is to develop and ultimately commercialize the first targeted therapy for triple negative breast cancer, which can be particularly aggressive and have a higher rate of recurrence and death than other subtypes of breast cancer.