Read about a small molecule inhibitor of mycobacterial lipid biosynthesis that Xuequan Lu and Jae-Sang Ryu have developed in collaboration with Luis Quadri's lab.
Congrats to Justin Cisar on his recent paper in J. Am. Chem. Soc.! VIEW(Highlighted in Faculty of 1000 Biology)
We've designed a novel class of macrocycles that inhibit non-ribosomal peptide synthesis enzymes selectively.
Sirkka Moilanen defended her thesis on May 14, 2007 and is now carrying out her postdoc with Prof. James Panek at BU. Congratulations, Sirkka!
Justin Potuzak defended his thesis on December 20, 2006 and is now carrying out his postdoc with Prof. Amos B. Smith III at UPenn. Congratulations Justin!
Diversity and Design – New Small Molecule Probes for Biology and Medicine
Small molecules are powerful tools for studying biological systems.
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.
Two approaches to identifying new small molecule ligands
However, the identification of new, highly specific small molecule probes remains a significant current challenge in chemical biology and drug discovery. We are engaged in a two-pronged approach to this problem involving both diversity-oriented synthesis (DOS) and rational design. In the first approach, novel combinatorial libraries are synthesized and used in high-throughput screens against a variety of biological targets. In the second approach, structural and mechanistic information about a selected biological target is used to guide the design of individual small molecule probes. 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.
Novel natural product-based libraries target underrepresented regions of chemical space
Our efforts in diversity-oriented synthesis are focused on generating 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 much 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, polyketide fragments, and multiscaffold polycyclics.
Salicyl-AMS is a new antibiotic lead compound to treat tuberculosis and plague
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 recently developed a potent inhibitor of enzymes required for iron uptake and virulence in pathogenic bacteria including Mycobacterium tuberculosis and Yersinia pestis. We are now pursuing analogs of this lead compound to develop new potential antibiotics. Notably, many pharmaceutical companies have drastically reduced their efforts in this area in recent years, increasing the need for continuing advances by academic researchers.
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 on our research, see our Projects page.
Diversity-Oriented Synthesis at MSKCC
The new MSKCC Zuckerman Research Center opened in summer 2006 and the Tan Lab moved into the top(21st) floor on September 27!
(top) Building construction from July 20, 2004 thru June 20, 2005. (bottom) The current view to the southeast from the 21st floor.
Research in the Tan Laboratory focuses on the diversity-oriented synthesis of combinatorial libraries based on natural products. These libraries are used in high-throughput screening to identify new chemical genetic probes for chemical biology and drug discovery. Keywords: diversity-oriented synthesis, dos, combinatorial, combinatorial chemistry, combinatorial library, combichem, natural product, natural products, chemical genetic, chemical genetics, pharmacology, chemistry, chemical biology, drug design, drug discovery, drug development, drug, high-throughput screening, hts, screening
Lab Head CV (PDF)
