The antiangiogenic properties of thalidomide reported by D'Amato and colleagues prompted its clinical evaluation in various solid tumors, including prostate cancer. Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenesis pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort in our laboratory. Previously, we showed that one of the products of cytochrome P450 2C19 isozyme biotransformation of thalidomide, 5'-OH-thalidomide, is responsible for the drug's antiangiogenic activity. Based on the chemical structure of this metabolite, we collaborate with Drs. Nigel Greig (NIA, NIH) and Michael Gutschow to synthesize novel thalidomide analogs, evaluate them using in vitro and in vivo models to assess activity, and characterize their structure-activity-relationships for further rational drug design. We have synthesized over 315 novel analogs of thalidomide and screened them for inhibition of inflammation and angiogenesis using various in vitro, ex vivo, and in vivo drug development models (e.g., rat aorta ring model, human saphenous vein model, cultured endothelial cells, migration and tube formation assays). In collaboration with Dr. Neil Vargesson, we conduct an in vivo screen of a library of new analogs to determine which agents demonstrate activity using the in vivo zebrafish and chicken embryo model systems. We identified the most potent of these agents and have patented them. We continue to develop these compounds, which appear to have minimal side effects in initial preclinical toxicology studies and may have improved pharmacology over the two FDA approved thalidomide analogs. We have optimized for both antiangiogenic and anti-inflammatory properties of these immunomodulatory drugs (IMiDS), which means the clinical indication can go beyond hematological malignancies and could have activity in solid tumors. This work in antiangiogenic/anti-cancer drug development serves not only to advance the field of antiangiogenic therapy but also to discover new treatment paradigms that focus on immunomodulation for advanced, metastatic disease. Development of HIF-1alpha inhibitors - The hypoxia-inducible factor (HIF) is fundamentally involved in tumor angiogenesis, invasion, and energy metabolism. Inhibition of HIF-1 represents an attractive therapeutic strategy for targeting hypoxia, a hallmark of many solid tumors, and tumor angiogenesis. One promising approach for directly inhibiting HIF-1 activity is by disrupting the tight binding between HIF-1a and p300. Previously, our laboratory developed an in vitro fluorescence binding assay that can be used in a high-throughput screen to identify small-molecule inhibitors of HIF-1a through inhibiting the binding interaction between the C-terminal transactivation domain (CTAD) of HIF-1a and the cysteine/histidine-rich 1 (CH1) domain of p300. Using our HIF-1a/p300 assay, we performed high-throughput screen of NCI's Natural Products Repository in collaboration with Dr. Kirk Gustafson (Molecular Targets Laboratory/NCI). This effort led to the discovery of a series of pyrroloiminoquinone alkaloids including discorhabdin and makaluvamine alkaloids, originating from a Latrunculia sp. of marine sponge, as potential HIF-1a/p300 inhibitors. Discorhabdins exhibit a plethora of biological properties, including strong cytotoxic, antimicrobial, antiviral, antimalarial, and immunomodulatory effects. Thus, research on the isolation, structural determination, and synthesis of these alkaloids has attracted considerable attention. We discovered two lead discorhabdins (discorhabdin H and discorhabdin L) with potent activity in inhibiting the interaction between the oncogenic transcription factor HIF-1a and the coactivator protein p300. We recently demonstrated that only discorhabdin L possesses excellent antiangiogenic activity in inhibiting endothelial cell proliferation and tube formation, as well as decreasing microvessel outgrowth in the ex vivo rat aortic ring assay. We further showed that discorhabdin L significantly inhibits in vivo prostate tumor growth in a LNCaP xenograft model. In conclusion, our findings suggest that discorhabdin L represents a promising HIF-1a inhibitor worthy of further drug development.
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