Small molecules targeting RuvBL complex for triple negative breast cancer

摘要 该项目的目标是开发RuvBL1/L2复合体的小分子调节剂，作为潜在的治疗方法 通过靶向DNA双链断裂(DSB)修复途径治疗三阴性乳腺癌(TNBC)。TNBC 是乳腺癌的一个亚型，其分子特征是缺乏雌激素受体的表达 (ER)、孕激素受体(PR)或HER2(人表皮生长因子受体2)扩增。脱氧核糖核酸 复制应激和活性氧物种普遍存在于TNBC细胞中，这是由于激活了各种 致癌基因。因此，TNBC细胞不断产生DSB。为了让TNBC细胞存活，这些致命的 必须修理DSB。因此，在癌症的发展过程中，TNBC细胞共同进化 有效的DSB修复机制，保护它们免受内源性致命DSB的伤害。因此，目标是 DNA修复通路已被认为是开发新的治疗方法的一种潜在的有力策略 TNBC。通过利用仅在TNBC细胞中普遍存在的内源性DSB的这一独特特征，这种疗法 可对TNBC细胞提供选择性毒性，而不损害正常细胞。我们最近发现了一部小规模的小说 分子先导化合物靶向RuvBL1/L2抑制TNBC细胞DSB修复在此应用程序中，我们 建议进一步开发这一用于治疗TNBC的小分子先导化合物，并有3个具体目标。 在目标1中，我们将研究这种新型先导化合物的作用机理。在目标2中，我们将对此进行优化 使用不同的药物化学策略的铅化合物。在目标3中，我们将研究优化后的 化合物在不同临床前模型中单独以及与PARP抑制剂联合使用时的抗TNBC效果。

Abstract The goal of this project is to develop small molecule modulators of RuvBL1/L2 complex as potential therapies for triple negative breast cancer (TNBC) by targeting DNA double-strand breaks (DSB) repair pathways. TNBC is a subgroup of breast cancer and is molecularly characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) or HER2 (human epidermal growth factor receptor 2) amplification. DNA replication stress and reactive oxygen species are prevalent in TNBC cells due to activation of various oncogenes. Thus, TNBC cells constantly generate DSBs. In order for the TNBC cells to survive, these lethal DSBs must be repaired. Accordingly, over the course of development of cancer, TNBC cells have co-evolved efficient DSB repair mechanisms that protect them from the endogenous lethal DSBs. Therefore, targeting DNA repair pathways has been proposed as a potentially powerful strategy to develop novel therapeutics for TNBC. By exploiting this unique feature of endogenous DSBs prevalent only in TNBC cells, such therapeutics can offer selective toxicity to TNBC cells without harming normal cells. We recently identified a novel small molecule lead compound to target RuvBL1/L2 to inhibit DSB repair in TNBC cells. In this application, we propose to further develop this small molecule lead compound for the treatment of TNBC with 3 specific aims. In aim 1, we will study the mechanism of action of this novel lead compound. In aim 2, we will optimize this lead compound using different medicinal chemistry strategies. In aim 3, we will investigate the optimized compounds' anti-TNBC efficacy in different preclinical models alone and in combination with PARP inhibitors.