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Department of Pharmacology

Houston, Texas

BCM students are involved in research.
Pharmacology
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Yongcheng Song, Ph.D.

Photograph of Dr. Yongcheng Song

Assistant Professor
Department of Pharmacology

ysong@bcm.edu

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

  • 2012-17, NIH/NINDS, R01NS080963 (PI)
  • 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:

  1. Drug discovery 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 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]) and J. Med. Chem. [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. These compounds were found to be able to induce differentiation and reduce the population of CSC.
  2. Chemical probes targeting mutant proteins relevant to cancer. For example, recent genetic studies show that a high frequency of IDH (isocitrate dehydrogenase) mutation was identified in low-grade glioma (>75%), acute myeloid leukemia (~20%) and other types of cancer. Biochemical studies as well as clinical evidence suggest IDH mutation plays important roles in cancer initiation and/or progression. We are using an integrated strategy of rational inhibitor design, X-ray protein crystallography and medicinal chemistry to develop novel chemical probes targeting IDH mutation and investigate the biological functions of mutant IDH in glioma or other cancers.
  3. Structure based approach to the discovery of novel small molecule inhibitors targeting multiple drug resistant pathogens. The non-mevalonate isoprene biosynthesis pathway 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]).

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

Group members

Postdocs: Lisheng Deng, Hong Jiang, Zhen Liu, Yuan Yao, Baisong Zheng, Li Zhang, Cong Wang, Bulan Wu

Graduate student: Justin Anglin

Representative publications:

  1. Anglin, J. L.; Deng, L.; Yao, Y.; Cai, G.; Liu, Z.; Jiang, H.; Cheng, G.; Chen, P.; Dong, S.; Song, Y.* Synthesis and Structure Activity Relationship Investigation of Adenosine-containing Inhibitors of Histone Methyltransferase DOT1L. J. Med. Chem., 2012, 55, 8066–8074. [link]
  2. Cai, G.; Deng, L.; Fryszczyn, B. G.; Brown, N. G.; Liu, Z.; Jiang, H.; Palzkill,T.; Song, Y.* Thermodynamic investigation of inhibitor binding to 1-deoxy-D-xylulose-5-phosphate reductoisomerase. ACS Med. Chem. Lett. 2012, 3, 496–500. [link]
  3. Yao, Y.; Chen, P.; Diao, J.; Cheng, G.; Deng, L.; Anglin, J. L.; Prasad, B. V. V.; Song, Y Selective Inhibitors of Histone Methyltransferase DOT1L: Design, Synthesis and Crystallographic Studies. J. Am. Chem. Soc., 2011, in press. Epub on-line [link]
  4. Deng, L.; Diao, J.; Chen, P.; Pujari, V.; Yao, Y.; Cheng, G.; Crick, D. C.; Prasad, B. V. V.; Song, Y Inhibition of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase by Lipophilic Phosphonates: SAR, QSAR and Crystallographic Studies. J. Med. Chem., 2011, 54, 4721-34. [link]
  5. Deng, L.; Endo, K.; Kato, M.; Cheng, G.; Yajima, S.; Song, Y. Structures of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase/Lipophilic Phosphonate Complexes. ACS Med. Chem. Lett., 2011, 2, 165-70. [link]
  6. Deng, L.; Sundriyal, S.; Rubio, V.; Shi, Z.; Song, Y.* Coordination Chemistry Based Approach to Lipophilic Inhibitors of 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase. J. Med. Chem., 2009, 52, 6539-42. [PubMed] [DOI] [link]
  7. Song, Y., Liu, C.I., Lin, F.Y., No, J.H., Hensler, M., Liu, Y.L., Jeng, W.Y., Low, J., Liu, G.Y., Nizet, V., Wang, A.H., Oldfield, E. Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: in vitro, in vivo, and crystallographic results. J. Med Chem., 2009, 52, 3869-80. [PubMed] [DOI]
  8. Song, Y.,Lin, F.Y., Yin, F., Hensler, M., Rodrígues Poveda, C.A., Mukkamala, D., Cao, R., Wang, H., Morita, C.T., González Pacanowska, D., Nizet, V., Oldfield, E. Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in Staphylococcus aureus. J. Med Chem., 2009, 52, 976-88. [PubMed] [DOI]
  9. Liu, C.I.; Liu, G.Y.; Song, Y.; Yin, F.; Hensler, M.; Jeng, W.-Y.; Nizet, V.; Wang, A.H.J.; Oldfield, E. A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence Science, 2008, 319, 1391-1394. (these authors contributed equally) [PubMed] [DOI]

Recruitment:

We have Postdoctoral Research Associate positions in Synthetic Organic Chemisrty, Protein Crystallography and/or Cancer Biology for talented and self-motivated researchers. If interested, please send your complete C.V. including a complete list of publications and contact information of three references to ysong@bcm.edu. For graduate applicants, please go to our department Graduate Program site for instruction.

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