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Diversity and Design Two approaches to identifying new small molecule ligands |
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Genome sequencing efforts and an increasingly molecular understanding of biology have revealed myriad new biological targets of both fundamental and potential therapeutic interest. Small molecules are extremely powerful tools for dissecting the functions of and evaluating the therapeutic potential of these targets using a pharmacological or 'chemical genetic' approach. However, the identification of new, highly specific small molecule probes remains a significant current challenge in chemical biology and drug discovery. This can be attributed to the fact that existing drugs address only a very small set of ≈200 human protein targets, and most probe and drug discovery efforts focus on a correspondingly narrow range of related chemical structures. To overcome these challenges, we are using two complementary approaches to ligand discovery involving both diversity-oriented synthesis and rational drug design. We leverage insights from biologically active natural products at multiple levels to guide these efforts. At the heart of our program lies a deep interest in advancing the frontiers of synthetic organic chemistry.
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Diversity-Oriented Synthesis Novel natural product-based libraries target underrepresented regions of chemical space |
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In the area of diversity-oriented synthesis, we are developing discovery libraries based on privileged structural motifs from natural products. Such structures have a demonstrated ability to bind multiple classes of biological targets, but have distinct structural and physicochemical properties compared to existing drugs. Thus, these libraries are designed to access complementary regions of chemical structure space and spectra of biological targets. Notably, many of the existing approaches to synthesizing these structures are unsuitable for diversity-oriented synthesis, due to the exceptional requirements for reaction efficiency and flexibility. Thus, we are presented with numerous opportunities to develop new chemical methodologies with broader applications in organic synthesis. Our current synthetic targets include spiroketals, polyketides, and alkaloid/terpenoid-like polycyclics.
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Rational Design Designed adenylation enzyme inhibitors such as salicyl-AMS are new potential antibiotics |
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In the area of rational design, we leverage knowledge of reaction mechanisms and protein structure to design new enzyme inhibitors. In particular, we have developed a series of sulfonyladenosine-based molecules as inhibitors of adenylation enzymes. Many of these enzymes are involved in biosynthetic pathways that are required for virulence in pathogenic bacteria, including Mycobacterium tuberculosis and Yersinia pestis. We have identified a number of promising lead compounds and are investigating their potential as new antibiotics. Notably, many pharmaceutical companies have abandoned their efforts in antibiotic discovery in recent years, emphasizing the need for continuing advances by academic researchers to combat the growing problem of antibiotic resistance. Recently, we have also applied similar strategies to dissecting the mechanism of eukaryotic E1 enzymes that catalyze key steps in ubiquitination and related processes.
We leverage multidisciplinary collaborations with biologists to evaluate the molecules we synthesize, with particular interests in cancer and infectious diseases. This collaborative approach brings together the strengths of both chemists and biologists and is a critical aspect of our program. Our Tri-Institutional Research Program, which encompasses Sloan–Kettering, Cornell University, and the Rockefeller University, provides an ideal environment for these efforts. The small molecule probes we discover are powerful tools for studying fundamental questions in biology and for validating new therapeutic targets in model systems. These molecules then provide valuable starting points for developing new mechanism-based therapeutics.
For more details, see our Research Projects page.
Lab Head CV (PDF)
