Diversity and Design – New Small Molecule Probes for Biology and Medicine
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Chemical Genetics Small molecules are powerful tools for studying biological systems. |
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Small molecules are extremely powerful tools for studying biological systems using a pharmacological or 'chemical genetic' approach. They provide rapid, conditional, dose-dependent, and often reversible control of biological functions. Thus, dynamic processes such as the cell cycle and development can be dissected in detail by adding or removing the small molecule at appropriate times. Moreover, in contrast to genetic knockouts and RNA knockdowns, selective small molecule probes can be used to study the individual functions of multifunctional proteins and can distinguish between different conformational and post-translational modification states of their targets. Small molecules can also be used to illuminate new potential therapeutic targets and provide a direct means of validating these targets in model systems.
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Diversity and Design Two approaches to identifying new small molecule ligands |
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However, the identification of new, highly specific small molecule probes remains a significant current challenge in chemical biology and drug discovery. We use a two-pronged approach to address this problem involving both diversity-oriented synthesis (DOS) and rational drug design. In the first approach, novel small molecule libraries are synthesized and tested against a variety of biological targets to identify new probes. In the second approach, structural and mechanistic information about a selected biological target is used to guide the design of an individual small molecule probe. These two approaches are complementary and, indeed, can often be combined productively. 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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Our efforts in diversity-oriented synthesis are focused on generating discovery libraries based on privileged structural motifs found in biologically active natural products. Such structures have a demonstrated ability to bind multiple classes of biological targets. Further, in contrast to widely available 'drug-like' libraries, these natural product-like libraries exhibit greater structural diversity and complexity. Thus, we expect that these libraries will 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 Salicyl-AMS is a new antibiotic lead compound to treat tuberculosis and plague |
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In the area of rational design, we are leveraging our knowledge of enzymatic reaction mechanisms and protein structural data to design new enzyme inhibitors. In particular, we have developed a series of sulfonyladenosine-based molecules as inhibitors 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 this area in recent years, emphasizing the need for continuing advances by academic researchers to combat the growing problem of antibiotic resistance.
We leverage multidisciplinary collaborations with biologists to carry out biological evaluation of the molecules we synthesize, particularly in the areas of 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 identify 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)
