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Structural and Computational Biology and Molecular Biophysics

Houston, Texas

A BCM research lab.
Structural and Computational Biology & Molecular Biophysics
not shown on screen

Yongcheng, Song Ph.D.

Photograph of Dr. Yongcheng SongAssistant Professor
Department of Pharmacology

Education and Employment

  • B.S., 1993, Inorganic Chemistry, Nanjing University (China)
  • Ph.D., 2001, Medicinal Chemistry, National University of Singapore
  • Postdoctoral, 2001-2002, Organic Chemistry, Tokyo Institute of Technology (Japan)
  • Postdoctoral, 2003-2004, Medicinal Chemistry, University of Illinois at Urbana-Champaign
  • Research Scientist, 2005-2008, University of Illinois at Urbana-Champaign
  • Assistant Professor, 2008-present, Baylor College of Medicine, Houston, TX

Awards/Grants

  • 2011-14, CPRIT (Cancer Prevention and Research Institute of Texas), RP110050 (PI)
  • 2010-12, NIH/NIAID, R21AI090190 (PI)
  • 2010-12, NIH/NIAID, R21AI088123 (PI)
  • 2010-15, NIH/NIAID, P01AI057788 (co-I)
  • 2010-13, CPRIT, RP100421 (co-I)
  • 2005-08, Leukemia & Lymphoma Society Special Fellowship
  • 2001-02, JSPS (Japan Society for the Promotion of Science) Postdoctoral Fellowship

Research Interests

In general, we are interested in rational design and development of small molecule inhibitors of novel, biologically important enzymes. These compounds will be exploited as chemical probes in vitro and in vivo (Chemical Biology), or further developed to become clinically useful drugs (Drug Discovery). These goals will be achieved by using a combination of rational, computational drug design, synthetic chemistry, high-throughput screening, molecular & cell biology and protein x-ray crystallography, as illustrated below.

Illustration of the process from drug design to drug final production

Our active research directions are:

  • Structure based approach to the design and discovery of novel small molecule inhibitors of non-mevalonate isoprene biosynthesis pathway, which is essential for most pathogenic bacteria and malaria parasites, but not present in humans and animals. For example, we have recently found, for the first time, a novel, lipophilic inhibitor of DXR (2nd enzyme in the pathway), which has a broad spectrum of antibacterial activity. In order to probe the hydrophobic nature of the DXR active site, we designed and found a series of lipophilic phosphonate DXR inhibitors. X-ray crystallographic studies reveal a new hydrophobic pocket as well as an important role of Trp211 in inhibitor recognition. Our DXR:inhibitor complex structures are useful for future design and development of lipophilic DXR inhibitors (read our papers in J. Med. Chem. [link] [link], ACS Med. Chem. Lett. [link] and J. Exp. Med. [link]).
  • Drug discovery targeting multiple drug resistant Gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter spp., Klebsiella pneumoniae and E. coli. Many strains of these pathogens have now been resistant to most antibiotics in the market and caused serious problems and mortalities in the clinic. We have now identified a class of compounds that effectively kill these bacteria and, importantly, their activity is not affected by any known antibiotic-resistant mechanisms.
  • Histone modifying enzyme inhibitors targeting cancer stem cells. Cancer stem cells (CSC) represent a small population of cancer cells that can initiate new cancer when transplanted to mice. CSCs (mostly in the G0 phase) are more resistant to conventional chemotherapeutics targeting rapidly dividing cancer cells and thus believed to be responsible for cancer relapse. Discovery of novel compounds targeting CSCs, while sparing normal stem cells, is therefore of importance. We are now using rational drug design and high-throughput screening to discover and develop novel epigenetic modulators targeting certain cancer (e.g., leukemia and breast) stem cells. We have recently discovered novel inhibitors of histone H3-lysine79 (H3K79) methyltransferase DOT1L (published in J. Am. Chem. Soc. [link]), which plays important roles in normal cell differentiation as well as the initiation and maintenance of leukemia with MLL (mixed lineage leukemia) gene translocations.

Postdocs: Guobin Cai, Pinhong Chen, Lisheng Deng, Jiasheng Diao, Hong Jiang, Yang Liu, Zhen Liu, Jian Xue, Yuan Yao.  Grad student: Justin Anglin

Representative publications:

  • Deng L, Zhang L, Yao Y, Wang C, Redell MS, Dong S and Song Y. Synthesis, Activity and Metabolic Stability of Non-Ribose Containing Inhibitors of Histone Methyltransferase DOT1L. Medchemcomm, 4(5):822-26 (2013). PubMed
  • Zheng B, Yao Y, Liu Z, Deng L, Anglin JL, Jiang H, Prasad BV and Song Y. Crystallographic investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase. ACS Med Chem Lett, 4(6):542-546 (2013). PubMed
  • Xue J, Diao J, Cai G, Deng L, Zheng B, Yao Y and Song Y. Antimalarial and Structural Studies of Pyridine-containing inhibitors of 1-Deoxyxylulose-5-phosphate Reductoismerase. ACS Med Chem Lett, 4(2):278-282 (2013). PubMed
  • Muhaxhiri Z, Deng L, Shanker S, Sankaran B, Estes MK, Palzkill T, Song Y and Prasad BV. Structural basis of substrate specificity and protease inhibition in Norwalk virus. J Virol, 87(8):4281-92 (2013). PubMed
  • Cai G, Deng L, Fryszczyn BG, Brown NG, Liu Z, Jiang H, Palzkill T and Song Y. Thermodynamic Investigation of inhibitor Binding to 1-Deoxy-D-Xylulose-5-phosphate Reductoisomerase. ACS Med Chem Lett, 3(6):496-500 (2012). PubMed
  • Anglin JL, Deng L, Yao Y, Cai G, Liu Z, Jiang H, Cheng G, Chen P, Dong S and Song Y. Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L. J Med Chem, 55(18):8066-74 (2012). PubMed
  • Chen P, Horton LB, Mikulski RL, Deng L, Sndriyal S, Palzkill T and Song Y. 2-Substituted 4.5-dihydrothiazole-4-carboxylic acids are novel inhibitors of metallo-ß-lactamases. Bioorg Med Chem Lett, 22(19):6229-32 (2012). PubMed

For more publications, see listings on PubMed.

Contact Information:

Department: Pharmacology
Address: Baylor College of Medicine
One Baylor Plaza
Room N520.08
BCM330
Houston, Texas 77030
Phone: 713-798-7415
Fax: 713-798-145
E-mail: ysong@bcm.edu

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