Discovery of BRG1 Inhibitors for Breast Cancer Therapy

描述（由申请人提供）：乳腺癌仍然是仅次于皮肤癌的美国妇女中最常见的癌症。美国癌症协会预测，2013年美国有超过225，000例乳腺癌新诊断和约40，000例乳腺癌死亡，在女性中仅次于肺癌死亡。乳腺癌的辅助和新辅助化疗是许多乳腺癌患者治疗方案的组成部分，目前临床使用许多药物和药物组合。这些药物中的许多靶向快速分裂的癌细胞中的增殖机制，而其他药物则干扰激素信号传导或其他信号转导途径。表观遗传调节蛋白的小分子抑制剂作为人类疾病的治疗剂已经被验证用于治疗其他癌症，并且仍然是快速扩展的研究领域。在这里，我们建议确定小分子抑制剂对以前的非靶向表观遗传调节，参与控制基因组DNA的可及性转录。BRG 1是一种ATP酶，是人类SWI/SNF染色质重塑酶复合物的催化亚基，是染色质结构和整个基因组可及性的重要调节因子。尽管它最初被标记为肿瘤 由于BRG 1是乳腺癌中的一种抑制蛋白，我们有强有力的证据表明，BRG 1在大多数人类乳腺肿瘤中过度表达，无论阶段或激素状态如何。我们发现，通过实验降低培养的乳腺癌细胞中的BRG 1水平，可以降低其在组织培养中的增殖速率，并大大降低，在某些情况下，当癌细胞原位植入小鼠乳腺脂肪垫时，可以防止肿瘤形成。减少细胞增殖和肿瘤发生的机制是BRG 1在表达脂质合成所必需的酶，特别是脂肪酸合成中的一般要求。重要的是，BRG 1水平降低的细胞显示出对乳腺癌治疗中使用的标准化疗剂和脂质合成抑制剂的敏感性增加。我们提供BRG 1染色质重塑酶作为乳腺癌治疗的重要新靶点。我们将开发和优化高通量，高含量的显微镜检测，用于发现小分子BRG 1抑制剂。这些药物将成为表观遗传乳腺癌化疗的新的候选药物。

DESCRIPTION (provided by applicant): Breast cancer remains second only to skin cancer as the most common cancer among women in the United States. The American Cancer Society predicts over 225,000 new diagnoses and about 40,000 deaths in the US from breast cancer in 2013, second in women only to lung cancer deaths. Adjuvant and neoadjuvant chemotherapies for breast cancer are an integral part of the treatment regimen for many breast cancer patients, with many drugs and combinations of drugs in current clinical use. Many of these drugs target proliferative mechanisms in rapidly dividing cancer cells, while others interfere with hormone signaling or other signal transduction pathways. Small molecule inhibitors of epigenetic regulatory proteins as therapeutics for human disease have been validated for treatment of other cancers and remain a rapidly expanding area of research. Here we propose to identify small molecule inhibitors against a previously untargeted epigenetic regulator that is involved in controlling genomic DNA accessibility for transcription. BRG1 is an ATPase that is a catalytic subunit of the human SWI/SNF chromatin remodeling enzyme complex, an important regulator of chromatin structure and accessibility across the genome. Despite its initial labeling as a tumor suppressor protein in breast cancer, we have strong evidence that BRG1 is over-expressed in most human breast tumors, regardless of stage or hormone status. We find that experimentally reducing BRG1 levels in cultured breast cancer cells reduces their rate of proliferation in tissue culture and greatly reduces, and in some cases prevents, tumor formation when cancer cells are orthotopically implanted in mouse mammary fat pads. The mechanism for the decrease in cell proliferation and tumor initiation is a general requirement for BRG1 in the expression of enzymes necessary for lipid, and specifically, fatty acid, synthesis. Importantly, cells with decreased BRG1 levels show increased susceptibility to both standard chemotherapeutic agents used in breast cancer treatment and to inhibitors of lipid synthesis. We offer the BRG1 chromatin remodeling enzyme as an important new target for breast cancer therapy. We will develop and optimize high-throughput, high-content microscopy assays for the discovery of small molecule BRG1 inhibitors. These will be novel candidate drugs for epigenetic breast cancer chemotherapy.