Category: Beeler, Aaron
In July, Aaron Beeler, joined BU Chemistry as a tenure-track Assistant Professor in medicinal chemistry. Aaron received his Ph.D. in 2002 from Professor John Rimoldi’s laboratory in the Department of Medicinal Chemistry at the University of Mississippi. In 2002, he joined John Porco’s laboratory as a postdoctoral fellow and in 2005 was promoted to Assistant Director for the Boston University Center for Chemical Methodology and Library Development (CMLD-BU). Professor Beeler has been an integral contributor to the highly successful operations of CMLD-BU which is successfully developing organic chemistry methodologies for the synthesis of complex molecules that are evaluated for biological activity. Among Aaron’s recent achievements has been the development of a microfluidic platform that has been utilized in the discovery of new reactions and complex molecular scaffolds for application in the synthesis of small molecule arrays.
Aaron brings his multidisciplinary expertise and experience in organic chemistry, engineering, and biology to address problems in medicinal chemistry related to human health. More specifically, research efforts in his laboratory will utilize microfluidics technology and organic synthesis to discover and optimize small molecules that will enable new therapies for diseases such as schizophrenia, Parkinson’s, cystic fibrosis, and cancer, as well as contributing to a deeper understanding of these conditions.
CMLD-BU researchers Bradley Balthaser, Meghan Maloney, Aaron Beeler, John Porco & John Snyder, in a paper published in the journal Nature Chemistry [23 OCTOBER 2011 | DOI: 10.1038/NCHEM.1178], present a new approach to accessing new, biorelevant structures by “remodeling” natural products. In this case, they demonstrate how the natural product derivative fumagillol can been remodeled to access a collection of new molecules using highly efficient chemical reactions.
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).