Development of p300/CBP histone acetyltransferase inhibitors for oncogene-driven cancers

开发用于癌基因驱动癌症的 p300/CBP 组蛋白乙酰转移酶抑制剂

• 批准号: 10627744
• 负责人: William C. Hahn
• 金额: $ 65.12万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-25 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627744
• 关键词: Androgens; Animal Model; Antineoplastic Agents; Binding; Biochemical; Biological Assay; Biophysics; CREBBP gene; CRISPR/Cas technology; Cancer Biology; Cancer Patient; Cancer cell line; Caring; Cell Line; Cell Lineage; Cells; Cellular Assay; Chemicals; Chemosensitization; Chromatin; Clinical; Complex; Credentialing; Development; Dose; Drug Kinetics; E1A-associated p300 protein; EP300 gene; Epigenetic Process; Estrogens; Experimental Genetics; Fluorescence Polarization; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Histone Acetylation; Histones; Human; Interdisciplinary Study; Knock-out; Libraries; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Modeling; Molecular Target; Monoclonal Antibodies; Mutate; Mutation; Oncogenes; Oncogenic; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Predisposition; Property; Prostate; Protein Inhibition; Recombinants; Recurrence; Reporting; Retinoic Acid Receptor; Series; Signal Pathway; Specificity; Structure; TMPRSS2 gene; Technology; Therapeutic; Transcription Factor Oncogene; Transferase; Tumor Subtype; Work; cancer cell; cancer initiation; cancer subtypes; cancer therapy; candidate validation; cell type; clinical development; cost effective; drug development; experience; fitness; follow-up; histone acetyltransferase; histone-binding proteins; improved; in vivo; inhibitor; insight; kinase inhibitor; lead candidate; lead series; member; meter; novel; patient population; patient stratification; pharmacologic; pre-clinical; response; scaffold; small molecule; small molecule inhibitor; structural biology; success; therapeutic target; tool; transcription factor; tumor growth; tumor initiation; tumor progression

Project Summary: Oncogene mutations frequently drive malignant transformation through inappropriate activation of regulatory kinases, and inhibitors that disrupt oncogenic phosphorylation have transformed care for subsets of cancer patients. Despite these successes, kinases are a small fraction of known oncogenes. In particular, several transcriptional factor oncogenes are essential for tumor initiation, progression and maintenance. In a few cases, targeting transcription factor oncogenes, such as estrogen, androgen and retinoic acid receptors, has led to clinically meaningful responses. However, direct targeting of most transcription factors has proven challenging. An alternative approach to directly targeting oncogenic transcription factors is to inhibit upstream epigenetic mechanisms regulating chromatin state. Indeed, many epigenetic regulators are recurrently somatically mutated, and several small molecules targeting chromatin regulators have been shown to abrogate tumor growth. In preliminary studies, we performed a gene expression-based screen to identify small molecules that inhibit the activity of TMPRSS2-ERG, a fusion oncogene leading to aberrant transcription in prostate cancer, and identified BRD4683, a highly potent inhibitor of p300 and CREB binding protein (CBP) histone acetyl transferase (HAT) activity. We have solved the structure of BRD4683 in complex with p300 and confirmed that inhibition of p300/CBP HAT activity is specifically required for survival of transcription factor-driven human cancer cell lines. Despite serving as a useful tool compound, BRD4683 has several chemical liabilities that limit its potential for drug development. We thus used BRD4683 to develop and validate a high-throughput and cost-effective biochemical screen for discovery of additional novel small molecule p300/CBP HAT inhibitors as well as a cascade of follow up- assays to eliminate false positives and prioritize chemically tractable molecules. In this project, we propose to identify new p300/CBP inhibitors and to systematically identify tumor subtypes dependent on combined p300/CBP HAT activity. In Aim 1, we will perform a high throughput biochemical screen of more than 800,000 compounds to identify new p300/CBP HAT inhibitors. In Aim 2, we will validate novel p300/CBP candidates using three complementary assays to identify inhibitors an IC50 of at least 10 µM. These assays will not only confirm inhibitor specificity but will also validate biochemical activity in cells. In Aim 3, we will perform iterative medicinal chemistry with the goal of identifying lead candidates. In parallel to these studies, we will perform both chemical and genetic experiments to systematically identify tumor subtypes that depend on p300/CBP HAT activity for cell fitness (Aim 4). To perform these studies, we have assembled a multidisciplinary research team with the necessary experience and expertise in cancer biology, structural biology, medicinal chemistry and drug development. We anticipate that these studies will allow us to identify small molecules that will serve as lead candidates that will spur the development of clinical grade p300/CBP HAT inhibitors and define which patient populations are likely to benefit from such inhibitors.

项目概要： 癌基因突变经常通过不适当地激活调节基因而导致恶性转化。 激酶和阻断致癌磷酸化的抑制剂已经改变了对癌症亚型的治疗 患者尽管有这些成功，激酶是已知致癌基因的一小部分。特别是几 转录因子癌基因是肿瘤发生、发展和维持所必需的。在少数情况下， 靶向转录因子癌基因，如雌激素、雄激素和视黄酸受体， 有临床意义的反应。然而，大多数转录因子的直接靶向已被证明具有挑战性。 直接靶向致癌转录因子的另一种方法是抑制上游表观遗传 调节染色质状态的机制。事实上，许多表观遗传调节因子是反复体细胞突变的， 并且几种靶向染色质调节剂的小分子已经显示出消除肿瘤生长。在 在初步研究中，我们进行了一个基于基因表达的筛选，以鉴定抑制肿瘤细胞增殖的小分子。 TMPRSS 2-ERG是一种导致前列腺癌异常转录的融合癌基因， BRD 4683，一种高效的p300和CREB结合蛋白（CBP）组蛋白乙酰转移酶（HAT）抑制剂 活动我们已经解析了与p300复合的BRD 4683的结构，并证实了对BRD 4683的抑制作用。 p300/CBP HAT活性是转录因子驱动的人癌细胞系存活所特别需要的。 尽管用作有用的工具化合物，但BRD 4683具有几种化学责任，这限制了其在生物降解方面的潜力。 药物开发 因此，我们使用BRD 4683来开发和验证高通量和具有成本效益的生化筛选 用于发现额外的新型小分子p300/CBP HAT抑制剂以及后续的级联反应- 分析以消除假阳性并优先考虑化学上易处理的分子。在这个项目中，我们建议 鉴定新p300/CBP抑制剂和系统地鉴定依赖于组合的 p300/CBP HAT活性。在目标1中，我们将进行超过80万的高通量生化筛选， 化合物，以确定新的p300/CBP HAT抑制剂。在目标2中，我们将使用以下方法验证新的p300/CBP候选物： 三种互补试验，以鉴定IC 50至少为10 µM的抑制剂。这些化验不仅能证实 抑制剂特异性，但也将验证细胞中的生物化学活性。在目标3中，我们将进行迭代药物治疗， 化学的目标是确定领先的候选人。在这些研究的同时，我们将进行两种化学 和遗传实验，以系统地鉴定依赖于细胞p300/CBP HAT活性的肿瘤亚型， 适应性（目标4）。 为了进行这些研究，我们组建了一个多学科的研究团队， 在癌症生物学、结构生物学、药物化学和药物开发方面的经验和专业知识。我们 预计这些研究将使我们能够确定小分子，这些小分子将作为主要候选人， 促进临床级p300/CBP HAT抑制剂的开发，并确定哪些患者人群可能 从这些抑制剂中获益。