Tagged: Thomas Gilmore
The Porco Research Group has received a 4-year, $1.2 million award from the National Institutes of Health for their proposal, Chemical Synthesis of Bioactive Flavonoid and Xanthone-Derived Natural Products.
Undertaken in conjunction with biological collaborators, including Professor Tom Gilmore (BU Biology) and Dr. John Beutler of the National Cancer Institute’s Center for Cancer Research, the goal of the research is to develop new chemical methodologies to enable the synthesis of bioactive flavonoid and xanthone-derived natural products that could lead to biologically active antitumor and anti-infective agents. Specifically, such agents will be useful as novel pharmacological therapies and as cytotoxic agents against both human cancers and malaria.
Their aims include total syntheses of anticancer agents such as the kuwanons and related prenylflavonoid Diels-Alder natural products as well as the bioactive tetrahydroxanthones blennolides A and B.
The award enables an exciting new research direction for Professor Porco and his collaborators involving the use of nanoparticles in organic reactions, asymmetric catalysis, and novel cycloaddition strategies.
There are many medically important drug targets that current drug discovery technology is not able to address. Collaborative basic research in Chemistry, Biology, and Biochemistry is key to solving these intractable problems to enable the discovery of new classes of drugs. A multidisciplinary team at Boston University, led by Associate Professor of Chemistry Adrian Whitty, aims to develop new approaches for challenging molecular targets. The National Institute of General Medical Sciences awarded this team a 4-year, $1.6 million grant entitled Design of Macrocyclic Inhibitors of the NEMO/IKKα/β Protein-Protein Interaction.
Only about 10% of the potential drug targets in the human genome have been successfully targeted with marketed drugs. Of the remaining 90%, many are intracellular proteins whose function is critically dependent on their reversible interactions with other proteins. Despite decades of effort by the pharmaceutical industry, developing oral drugs that inhibit protein-protein interactions (PPIs) has rarely succeeded and has become recognized as a major scientific and technological challenge.
The primary goal of this project is to determine whether the use of a class of natural product-inspired compounds called macrocycles constitutes a broadly applicable method for developing oral drugs against PPI targets. As a first challenge, the team is attempting to develop macrocycles that block the activity of NEMO, a key component of the IKK complex that activates NF-κB signaling. Chronic hyperactivity of the NF-κB pathway is associated with many human inflammatory diseases and cancers. Thus, the development of drug-like inhibitors of this pathway is highly relevant to public health.
The work will determine whether appropriately designed synthetic macrocycles can inhibit PPI targets while maintaining good drug-like properties. In terms of NF-κB and disease, their work will provide a means for testing whether inhibiting the interaction of NEMO with IKK—as a more targeted alternative to completely ablating all IKK activity—represents a useful new approach for attenuating inflammation.
In addition to Professor Whitty (quantitative biochemistry and drug discovery), the multidisciplinary research team comprises Professors Sandor Vajda and Dima Kozakov (computational chemistry), John Porco and Aaron Beeler (macrocycle synthesis), Karen Allen (X-ray crystallography), and Tom Gilmore (NF-κB pathway biology).