Developing Novel Pharmacological Interventions to Treat Leukemia

Yongcheng Song (320x240)
Dr. Yongcheng Song, Department of Pharmacology

Dr. Yongcheng Song, associate professor in the Department of Pharmacology at Baylor College of Medicine, has focused his research efforts on the rational design and development of small molecule inhibitors of biologically important proteins targeting cancers and infectious diseases. One of the main projects in Dr. Song’s group has been toward the development of novel compounds to treat acute leukemia by targeting leukemic stem cells (LSCs), a small population of leukemia cells that can initiate new cancer when transplanted into a new host. LSCs are responsible for chemotherapy resistance.

Acute leukemia with MLL (mixed-lineage leukemia) gene translocations accounts for approximately 75 percent of infant and 10 percent of child/adult acute leukemia. This subtype of leukemia has a poor prognosis with a five year survival rate of less than 40 percent. Unfortunately, intensified chemotherapy does not significantly improve survival, and its toxic side effects and associated patient suffering cannot be overlooked. Therefore, novel and effective targeted therapies for MLL-rearranged leukemia are desperately needed.

The objective of Dr. Song’s research is to discover and develop novel agents that selectively target LSCs driven by MLL oncogenes, but do not affect functions of normal bone marrow cells. They chose to target DOT1L, a protein that is essential for survival and proliferation of the LSCs. Utilizing rational drug design and medicinal chemistry, they have obtained, for the first time, several potent DOT1L inhibitors that demonstrate selective activity against the LSCs. Dr. Song’s most recent work in this area has yielded the synthesis of cyclopentane containing compounds that potently inhibit human DOT1L. More importantly, these particular compounds are metabolically stable in plasma and liver microsomes, and thus may be promising drug candidates for clinical applications.

The DOT1L project is one successful example of Dr. Song’s chemical biology and drug discovery program. Besides targeting cancer stem cells, his research interests also include developing chemical probes against mutant proteins relevant to cancer and discovery of novel small molecule inhibitors targeting multiple drug resistant pathogens.


• For the first time, potent, highly selective, and stable small molecule inhibitors have been developed targeting DOT1L.

• The novel drug design platform to develop DOT1L inhibitors can be applied to target novel targets in cancers and other human diseases.

• The researchers take a multipronged approach for drug development by using a combination of rational, computational drug design, synthetic chemistry, protein x-ray crystallography, high-throughput screening, and biological activity testing.

BLG Project Manager

Brian Phillips (