Positions
- Professor
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Pharmacology and Chemical Biology
Baylor College of Medicine
Houston, TX, US
- Faculty Senator
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Baylor College of Medicine
Houston, Texas, United States
- Member
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Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas, United States
Education
- Post-Doctoral Fellowship at University Of Illinois, Urbana-Champaign
- 01/2003 - Urbana, Illinois, United States
- Post-Doctoral Fellowship at Tokyo Institute Of Technology
- 01/2001 - Tokyo, Japan
- PhD from National University Of Singapore
- 10/2000 - Singapore, Singapore
Professional Interests
- Drug Discovery, Medicinal Chemistry and Chemical Biology
Professional Statement
We are interested in discovery and development of novel small molecule inhibitors of biologically important proteins, targeting cancer and infectious diseases. These compounds will be used as chemical probes to find new cancer biology (Chemical Biology), or further developed to become clinically useful drugs (Drug Discovery). These goals will be achieved by using a combination of compound screening, rational drug design, medicinal chemistry, biochemical/physical (including X-ray and NMR) studies, and biological (in vitro and in vivo) activity testing.
Our currently active projects include
1. Novel chemical probes targeting epigenetic (histone/DNA modification) proteins and aberrant gene expression in cancer: We have recently discovered novel inhibitors of histone H3-lysine79 (H3K79) methyltransferase DOT1L, H3K4 demethylase LSD1, and histone acetyltransferase p300/CBP. These compounds were found to inhibit aberrant gene expression pathways (regulated by these epigenetic proteins) and have selective activity against MLL-rearranged leukemia and other cancers. We are actively exploring functions of several other epigenetic proteins in cancer, designing and synthesizing potent and selective inhibitors as potential therapeutics.
2. Chemical probes targeting critical protein-protein interactions in MLL-rearranged leukemia and other cancers. In addition to epigenetic regulation, protein-protein interactions (PPI) in certain transcription complexes are critical to aberrant gene expression in cancer, such as super elongation complex (SEC), a protein complex consisting of transcription cofactors AF9/ENL, AF4/AFF4, ELL and P-TEFb. PPIs in SEC are essential for gene expression in MLL-rearranged leukemia, other cancers and HIV infection, but dispensable in normal cells. We are discovering and developing potent and selective inhibitors of these PPIs as potential therapeutics. Proteolysis-targeting chimera (PROTAC) technology is also applied to efficiently degrade these proteins.
3. Drug discovery targeting SARS-CoV-2, Flavivirus (Zika/Dengue/West Nile) and other viruses, which are important human pathogens. Through compound screening followed by medicinal chemistry, novel compounds were identified, for the first time, to be potent and drug-like inhibitors of Zika/Dengue/West Nile and SARS-CoV-2 virus proteases. These compounds exhibited potent in vitro and in vivo antiviral activity. Optimization of activity as well as drug properties is on-going, in an effort to find drug candidates to prevent and treat these viral infections.
Our currently active projects include
1. Novel chemical probes targeting epigenetic (histone/DNA modification) proteins and aberrant gene expression in cancer: We have recently discovered novel inhibitors of histone H3-lysine79 (H3K79) methyltransferase DOT1L, H3K4 demethylase LSD1, and histone acetyltransferase p300/CBP. These compounds were found to inhibit aberrant gene expression pathways (regulated by these epigenetic proteins) and have selective activity against MLL-rearranged leukemia and other cancers. We are actively exploring functions of several other epigenetic proteins in cancer, designing and synthesizing potent and selective inhibitors as potential therapeutics.
2. Chemical probes targeting critical protein-protein interactions in MLL-rearranged leukemia and other cancers. In addition to epigenetic regulation, protein-protein interactions (PPI) in certain transcription complexes are critical to aberrant gene expression in cancer, such as super elongation complex (SEC), a protein complex consisting of transcription cofactors AF9/ENL, AF4/AFF4, ELL and P-TEFb. PPIs in SEC are essential for gene expression in MLL-rearranged leukemia, other cancers and HIV infection, but dispensable in normal cells. We are discovering and developing potent and selective inhibitors of these PPIs as potential therapeutics. Proteolysis-targeting chimera (PROTAC) technology is also applied to efficiently degrade these proteins.
3. Drug discovery targeting SARS-CoV-2, Flavivirus (Zika/Dengue/West Nile) and other viruses, which are important human pathogens. Through compound screening followed by medicinal chemistry, novel compounds were identified, for the first time, to be potent and drug-like inhibitors of Zika/Dengue/West Nile and SARS-CoV-2 virus proteases. These compounds exhibited potent in vitro and in vivo antiviral activity. Optimization of activity as well as drug properties is on-going, in an effort to find drug candidates to prevent and treat these viral infections.
Selected Publications
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Yao Y, Chen P, Diao J, Cheng G, Deng L, Anglin JL, Prasad BV, Song Y. " Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies. " J. Am. Chem. Soc.. 2011 Oct 26; 133 (42) : 16746-9.
Pubmed PMID: 21936531. -
Liu, Z.; Yao, Y.; Kogiso, M.; Zheng, B.; Deng, L.; Qiu, J. J.; Dong, S.; Lv, H.; Gallo, J. M.; Li, X.-N.; Song, Y.. " Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, SAR and Selective Antitumor Activity " J. Med. Chem.. 2014 ; 57 : 8307-18.
Pubmed PMID: 25271760. -
Wu, F.; Zhou, C.; Yao, Y.; Wei, L.; Feng, Z.; Deng, L.; Song, Y.. " 3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1. " J. Med. Chem.. 2016 ; 59 : 253.
Pubmed PMID: 26652247. -
Wu, F.; Zheng, B.; Jiang, H.; Kogiso, M.; Yao, Y.; Zhou, C.; Song, Y.. " Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds. " J. Med. Chem.. 2015 ; 58 : 6899.
Pubmed PMID: 26280302.
Projects
- Drug Discovery Targeting SARS-CoV-2, Zika and Dengue Viruses
- Chemical Probes Targeting Critical Protein-Protein Interactions in MLL leukemia and other cancers
- Small-Molecule Modulators Targeting Epigenetic Proteins and Aberrant Gene Expression in Cancer
Funding
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Antiviral Drug Discovery Targeting Zika Virus Protease
#W81XWH-18-1-0368 (PI) - Grant funding from DOD/CDMRP
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Novel small-molecule inhibitors of SARS-CoV-2 protease
#R21AI159323 (PI) - Grant funding from NIH/NIAID
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Novel Small-Molecule Probes Targeting Oncogenic Fusion MLL in Pediatric Leukemia
#R01CA266057 (PI) - Grant funding from NIH/NCI
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