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

项目总结:

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.